InstItute of GenetIcs

2o10
Institute of Genetics &
Molecular &
Cellular Biology
contents
Foreword
2
Academics
4
Development & Stem Cells
6
Cancer & Functional Genomics
34
Integrated Structural Biology
62
Translational Medicine & Neurogenetics
80
ICS
100
Platforms
102
Core facilities
108
Facts & Figures
110
Staff scientists 112
Prizes & Distinctions 116
Publications until June 2010 117
Publications 2009
120
Where we are
126
Olivier Pourquié, IGBMC Director
Foreword
The IGBMC is one of the leading centers in biological research in Europe. It was founded in 1994
by Pierre Chambon, one of the world’s leading
figures in biomedical sciences. With its 768 staff
the Institute represents one of the largest French
biomedical research units associating INSERM,
CNRS and the University of Strasbourg. The
IGBMC is located close to Strasbourg, a cosmopolitan city hosting the European parliament on
the frontier between France and Germany.
The IGBMC is a highly international center with
48 different nationalities represented among its
personnel and all activities in the Institute are carried out in English.
The 43 independent research teams work on a
broad array of topics, ranging from the analysis of
protein structure to human genetics. The research
themes are organised into the following four
transversal Programmes. The Integrated Structural
Biology Programme consists of teams studying the
structure of proteins using a variety of approaches
ranging from diffraction analysis and computer
modeling to state of the art electron microscopy.
The Programme Functional Genomics and Cancer
is centered on the analysis of the regulation of gene
expression and epigenetics. Several groups in this
Programme are also interested in the deregulation
of these mechanisms that often lead to cancer. The
Programme Development and Stem Cells brings together research groups interested in the formation
of the embryo and in stem cell biology in a variety
of model systems. Within this Programme, we
also see an interface emerging with the physical
sciences, associating physicists and cell biologists
in the study of complex processes such as morphogenesis. The Programme Translational Medicine and Neurogenetics links all the research teams
that are directly interested in biological questions
with immediate clinical relevance, such as human
genetic diseases.
One of IGBMC’s major assets are its excellent
core facilities and its outstanding technological
platforms, which provide accessible state of the
art technologies to the institute’s scientists. One
of these platforms, the Mouse Clinical Institute
(ICS), is rather unusual in that it is a large structure employing more than 100
people exclusively dedicated to
43 Groups
mouse technology. Its activities
106 Staff scientists
range from transgenic mouse
models production to complex
121 Postdoctoral fellows
phenotyping strategies inclu118 PhD students
ding behavioral and metabolic
37 Master students
analyses. In the following pages
293 Engineers &
you will find an overview of
Technicians
IGBMC’s broad range of re
93 Administrators &
search activities and technology
General services
support, highlighting our stimulating environment which
aims to foster excellent training
and cross-discipline collaborations. <
With the ambition of creating a European centre of excellence in medical research, the IGBMC was founded by
Pierre Chambon and installed on its present site in 1994
with the assistance of INSERM, CNRS, the University
of Strasbourg and the American laboratories of Bristol
Myers-Squibb (BMS). Between 2002 and 2009, following
on from Pierre Chambon, the Direction of the IGBMC
was assured by Dino Moras and Jean-Louis Mandel, two
scientists of international reputation.
In October 2009, Olivier Pourquié, a pioneer in research
on muscles and skeletal development, elected to return to
France to lead the IGBMC, following several years spent
in the United States at the Howard Hughes Medical Institute. His principal objective is to confirm and strengthen
the status of the IGBMC on the national and international
scientific stage.
3
academics
academics
● Students & Post-docs Board
With its recently launched International PhD
Programme, the IGBMC successfully attracts and
recruits outstanding students from around the
world via a call for applications. In this framework,
we provide dedicated scientific and socio-professional training to our students, in accordance with the
Graduate School. The training benefits notably from
the excellent scientific environment and is tailored to
the needs of the students. The courses typically cover all areas of modern biology and state-of-the art
technologies offered at the Institute. The training of
our students is further enriched by a great diversity of
additional activities, of which a flavor is given here:
Since October 2004, the Students and Post-Docs
Board (SPB) of the IGBMC has been working actively
to promote and enhance the scientific and social exchange between the students and post-docs of the Institute, the scientific programmes, the core facilities as
well as the platforms. It also links IGBMC’s students/
post-docs with the Direction, and the Life Sciences
Graduate School of the University of Strasbourg. After
six years of continual growth and improvement, the
SPB has become an important partner working in a
close relationship with the IGBMC administration.
• Special Seminar Series: Eminent international
scientists are invited to give a lecture as part of the
IGBMC Special Seminar Series.
● Training at IGBMC
As one of the leading European centers for biomedical research, the IGBMC provides an outstanding research and training environment. With 239 students
and post-docs from over 40 countries, we offer a very
lively and dynamic setting, fostering interactions at
the IGBMC and beyond.
The IGBMC accepts about 37 Master Students and
25 PhD students annually, who are exposed to the
latest technological developments and are trained under the supervision of IGBMC group leaders across
the Institute’s broad range of research fields. The students are generally enrolled at the Life Sciences Graduate School of the University of Strasbourg, which
oversees the thesis progress and delivers the PhD certificate. Several IGBMC researchers teach at the University, including the medical school, thereby promoting links between the University and IGBMC.
• Student Special Lecture: Students have the
opportunity to invite an outstanding scientist to give
the Student Special Lecture.
• Award: Each year, a student is awarded a travel
fellowship to attend a scientific meeting.
• International meetings: Scientific meetings are
organized on a regular basis and provide our younger
researchers with the opportunity to meet outstanding
speakers from different fields.
• Guides: Three guides have been developed to
facilitate a newcomers’ life: a welcome guide, living
in Strasbourg, information guide about the University
and the Graduate School and fellowships.
• International Cine-Club: Launched in December
2007, the Cine-Club invites staff to discover and
learn from cultures that are represented at IGBMC.
Movies are selected and introduced by a student/postdoc from abroad that is willing to share some cultural
aspects about his or her country.
• French and English lunches: Once a month, the SPB
arranges a lunch to allow participants to practice their
language skills: speaking either French with native
French speakers or English with English natives.
• Social events: The SPB often organizes parties and
sport events to bring together students and post-docs
to strengthen bonds and to promote interactions in a
different setting.
• Lunches with prominent scientists: Students have
the opportunity to lunch with the Special Seminar
speakers in an informal setting.
• Internal seminars and retreats: Internal seminars give
students and post-docs the opportunity to present all
of their work to IGBMC. Retreats organized by the
scientific Programme offer a more informal setting to
present findings and to discuss and share knowledge
with more senior scientists.
• Seminars: We organize career development seminars
for our community.
• Retreats: In June 2010, the SPB organized the first
retreat for students and post-docs in a relaxed setting
in the Vosges Mountains.<
The SPB organizes the following activities:
• Poster sessions: On a monthly basis, students and
post-docs present their research projects. Staff from
core facilities and platforms are also invited to present
their activities.
• Scientific workshops: Three workshops are organized
every year with the assistance of platforms and
researchers of the Institute. Topics includes: Microarray
Analysis; Bioinformatics in the post-genomics area;
3D Structure Visualization and Functional Genomics.
Two of these workshops have been part of the training
within the IGBMC International PhD Programme
since 2009.
The International PhD Programme
Programme Coordination: Dr. Astrid Lunkes
PhD Programme Committee:
Dr. Elisabeth Georges-Labouesse, Dr. Sophie Jarriault,
Dr. Hélène Puccio, Dr. Evi Soutoglou, Dr. Laszlo Tora,
Dr. Bernardo Reina-San-Martin, Dr. Marat Yusupov
Student affairs: Dr. Katia Befort
The PhD Programme Administrator: Laetitia Gonzalez
Students & Post-doc Board
Coordination & communication: Irène Yujnovsky
Workshop: Fabrice Klein
Alumni & guides: Pierre Antony, Johann Boehm
Information package: Angelita Simonetti,
Thomas Hussenet
Web site: Florent Colin, Pierre-Eric Lutz
Poster sessions: Thomas Daniel, Jérôme Mastio,
Adrien Rousseau
Events: Sara Milosevic, Elisabeth Daguenet,
Martin Moune-Dimala
5
Unravelling the mystery of cell differentiation
"Understanding how cells differentiate and how they organize in
a 3-dimensional space should enable us to find tools to regenerate
human tissues, or to reduce the risk of cancer". M. Labouesse
The Development and Stem Cells Programme features 12 teams using the fruit fly,
zebrafish, worm, chicken and the mouse as
models of interest. The unifying theme of
the Programme is cell plasticity, either at the
nuclear level as it pertains to the mechanisms
that control stem cell maintenance and cell
fate reprogramming, or at the cellular level,
with regard to the mechanisms that control
cell shape changes during morphogenesis.
While we all focus on fundamental issues,
most of us develop models of human diseases such as, cardiovascular diseases, retinal
degeneration, scoliosis, Crohn’s disease, diabetes, infertility and cancer, among others.
Stem cells and reprogramming
Currently two- thirds of the teams aim to define the genetic and epigenetic Programmes
Development
& Stem cells
Mouse and chicken
•Pancreas development and diabetes
•Integrin signaling in organ morphogenesis
•Retinoic acid signaling and neuronal cell fate
•Role of retinoic acid signaling in germ cell specification
• Progenitor germ cells and iPS
•Somitogenesis and PSM extension
•Epigenetic marks in maintenance of blastomere identity
Zebrafish
•Somitogenesis
•Blood flow and cardiovascular development
•Cilia in development
Fruit fly
•Role of miRNAs in neural differentiation
•Collective cell migration
•Choice between glial and neuronal differentiation
Worm
•Cell fate reprogramming
•Impact of cell division on cellular potential
•Secretion and lumen formation
•Forces in embryonic morphogenesis
Physics and biology
•In vitro modeling of cell shape change
•Cytokinesis in fission yeast
that characterize the toti/pluripotence of
stem cells. Some specific questions are
“How do early mouse blastomeres remain
totipotent?”, “how are pancreas endocrine
cells made different from each other?” “How
does a pluripotent progenitor restrict its
potential to generate only glial or neuronal
progenitors?” “How do germ cells differentiate into male and female
gametes?” “How do muscle
13 Groups
precursors arise from the
23 Staff scientists
presomitic
mesoderm?”,
“how does a cell reprogram
31 Postdoctoral fellows
its identity?” The different
23 PhD students
labs approach these ques
tions through a combination
33 Engineers/Technicians
of genetic and cell biology
1 Assistant
analyses in mouse, chicken,
zebrafish, fly, worm, as well
as high throughput proteomic and sequencing methods.
Morphogenesis
Other teams aim to understand how cells
communicate during late stages of embryogenesis when organs achieve their final
functional shape. Imaging and cell biology
are central to the approaches developed and
more recently, the input of physics has become key to these developments. Some specific questions being asked are “How do cells
collectively migrate to their final positions?”
“How do cells interact with the extracellular
matrix to define organ shape?” “How does
a cell change its shape?” and “What is the
impact of forces on organ formation?” n
7
highlights
• Central Nervous System Patterning: We
revealed that retinoic acid acts antagonistically
to FGFs, but is required to potentiate Sonic hedgehog signaling, during elongation of embryonic trunk structures and patterning of the neural
tube.
shaping the future
Roles of retinoic acid
in mouse development and physiology
Further work will aim at elucidating common molecular
mechanisms operating during neurogenesis within the
developing telencephalon and the sensory neurons. This
work will also contribute to an understanding of molecular
pathways under retinoic acid control that are involved in
neural progenitor renewal, fate and differentiation. The
pathophysiological consequences of manipulating retinoic
acid production or RAR/RXR signaling in specific cell
populations will also be investigated. <
●Sensory Organ Development: Several molecular
and cellular alterations resulting from invalidated retinoic acid signaling within the embryonic
retina, the inner ear, and the olfactory placode
were characterized in our laboratory.
1
probing complexity
Development of the vertebrate nervous system results
from an interplay between all major embryonic signaling
pathways and requires coordination of many embryonic
events including axial patterning, lateral inhibition, progenitor fate determination, axonal guidance, and ectomesenchymal transformation giving rise to neural crest. Sensory
systems are formed by direct out-growth and evagination
of brain neuroepithelium in the case of the retina, and the
inductive processes leading to the formation of ectodermal placodes generating the lens, the embryonic inner ear
(otocyst), and the prospective olfactory epithelium.
Our team is interested in deciphering some of the highly
pleiotropic functions of the vitamin A derivative retinoic
acid, and its nuclear receptors (RARs/RXRs), in these
processes. We are using the mouse and chicken systems
to invalidate specific actors of this signaling pathway using
targeted gene inactivation, as well as pharmacological and
siRNA approaches. This work permits us to show that the
fine tuning of the activity of two classes of enzymes catalyzing the synthesis (retinaldehyde dehydrogenases), or
the catabolism (CYP26 cytochromes), of retinoic acid in
specific cell populations, is critical for the development of
the central nervous and sensory systems. <
Pascal Dollé
Studying developmental genes:
When «collinearity»
leads to complexity
●Brain Development and Physiology: We unravelled specific roles of retinoid signaling in higher
brain functions including motor control, cognitive functions and emotional processing. We
found that RARbeta signaling controls the development of a subpopulation of dopaminoceptive
neurons in the striatum involved in motor control, and
that RXRgamma inactivation results in depressive behavior due to impaired dopamine D2 receptor function in
the nucleus accumbens.
Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M, Gobaille S, Muramatsu S, Krezel W. Retinoid X Receptor
Gamma Control of Motivated Behaviours involves
Dopaminergic Signalling in Mice.
Neuron. 66:908-920. (2010).
●Mouse Models: Novel conditional alleles were generated
to study the function of the main retinol dehydrogenase
acting during development, and to assess the roles of retinoids produced by specific neuronal populations and by
the meninges. n
1- Analysis of neuronal progenitor
subpopulations in the developing
cerebral cortex.
2- Distribution of stem cells (green)
among differentiating heart myocardial
cells (red).
Lin SC, Dollé P, Ryckebüsch L, Noseda M, Zaffran S,
Schneider MD, Niederreither K. Endogenous retinoic
acid regulates cardiac progenitor differentiation.
Proc Natl Acad Sci U S A. 107(20):9234-9. (2010).
Ribes V, Le Roux I, Rhinn M, Schuhbaur B, Dollé P.
Early mouse caudal development relies on crosstalk between retinoic acid, Shh and Fgf signalling
pathways. Development. 136(4):665-76. (2009).
Niederreither K, Dollé P. Retinoic acid in development: towards an integrated view.
Nat Rev Genet. 9(7):541-53. (2008).
Pascal Dollé received his medical degree
in 1992 at Louis Pasteur University in
Strasbourg, France. Following a research
internship on developmental biology and
embryology with Denis Duboule and Pierre
Chambon, he obtained a PhD in1992 on
the developmental expression features
of murine Hox genes and was one of the
pioneers of the study of knock-out mice in
this gene family. In parallel, Pascal worked
on the characterization of retinoic acid
receptors function during development. In
1992, he joined Pierre Chambon’s team and
characterized several functions of RALDH2,
a key enzyme involved in retinoic acid
synthesis during embryogenesis. In 2001, he
created his own team whose current focus is
on the development of the nervous system
and sensory organs. n
2
9
highlights
• We have found that α6β4 integrin in the hemidesmosome is essential for epidermal/dermal
attachment. This integrin and laminin ligands
are implicated in genetic forms of epidermolysis
bullosa in human patients.
• By studying double-mutant mice for integrins to overcome functional redundancy, we
have been able to reveal novel roles for this family in tissue morphogenesis processes such as
formation of the apical ectodermal ridge in the
limb and neural tube closure.
1
probing complexity
Tissue morphogenesis and function involve changes in cell
shape, cell adhesion and migration. These events which
implicate cell-cell or cell-extracellular matrix (ECM) interactions are tightly regulated.
We are interested by cell-ECM interactions mediated by
the integrin family of adhesion receptors. By binding specific ECM ligands through their extracellular domains and
recruiting signaling molecules and cytoskeletal elements in
the cytoplasm, integrins serve as sensors of the milieu for
the cells and participate in the building of the appropriate
cellular responses.
Perturbations of integrins/ECM lead to severe pathological conditions (developmental defects, congenital muscular dystrophies, skin blistering and cancer). Our goal is to
understand the cellular and molecular mechanisms of integrin activity in vivo and address questions such as tissue
and stage requirements of integrins, ligand specificity in
vivo, signaling pathways, relevance to human pathologies.
To this end, we have mostly used mouse genetics.<
shaping the future
Integrin function and signaling in tissue
morphogenesis, integrity and homeostasis
Currently we concentrate our efforts on the role of integrins
in the epithelial tissues of skin and intestine. Of interest
is the fact that in adults these two tissues also undergo
tissue renewal and are submitted to mechanical forces.
Both epithelia possess hemidesmosomes. These anchoring
junctions at the basal pole of cells are molecular complexes
which play a crucial role in the control of epithelial cell
shape and polarity. In particular, they ensure the link with
the basement membrane outside the cell and the keratin
cytoskeletal network inside the cells. These junctions
are also important in tissue integrity during stress. Using
mouse genetics and cellular approaches, we hope to gain
insight about the signaling pathways that are implicated in
the formation and function of these junctions.<
Elisabeth Georges-Labouesse
Cellular and development
biology in vivo
• Our team was the first to elucidate the role of
an integrin in brain and retinal layer organization.
• We have found that the Nck interacting kinase (NIK)
is a molecular partner for integrin β1. Our recent studies
suggest that it is the α5β1 integrin heterodimer, a fibronectin receptor, which interacts with NIK, notably during
neuronal migration. n
Marchetti G, Escuin S, van der Flier A, De Arcangelis
A, Hynes RO, Georges-Labouesse E. Integrin alpha5beta1 is necessary for regulation of radial migration
of cortical neurons during mouse brain development
Eur J Neurosci. 31:399-409. (2010).
Wu C, Ivars F, Anderson P, Hallmann R, Vestweber D,
Nilsson P, Robenek H, Tryggvason K, Song J, Korpos
E, Loser K, Beissert S, Georges-Labouesse E, Sorokin LM. Endothelial basement membrane laminin
alpha5 selectively inhibits T lymphocyte extravasation
into the brain. Nat Med. 15(5):519-27. (2009).
1- Localisation of integrin α6 at the
basal pole of the basal keratinocytes
and hair follicle in skin. A mouse skin
section was stained with an antibody
against α6 integrin (green). DAPI
staining (blue) labels nuclei.
2- Plectin (red) and actin cytoskeleton
(green) of a migrating Caco2 cell.
Rodius S, Indra G, Thibault C, Pfister V, Georges-Labouesse E. Loss of alpha6 integrins in keratinocytes
leads to an increase in TGFbeta and AP1 signaling
and in expression of differentiation genes.
J Cell Physiol 212(2):439-49. (2007).
Haubst N, Georges-Labouesse E, De Arcangelis A,
Mayer U, Gotz M. Basement membrane attachment
is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes.
Development 133(16):3245-54. (2006).
After earning a master’s degree in Virology,
Elisabeth Georges-Labouesse obtained her
PhD at the Pasteur Institute UPMC (Paris)
on cutaneous papillomavirus and analyzed
the viral Programme, which depended on
epidermal cell differentiation steps. She
became a CNRS research associate in 1985
and was appointed a post-doctoral position
in 1989 at MIT, Cambridge, US with Richard
Hynes. While conducting her research at MIT,
she focused on the role of extracellular matrix proteins in tissue architecture by using
mutant mice. Her findings showed that fibronectin was involved in somite organization. In 1996 she discovered the essential
role of a6 integrin in hemidesmosomes for
dermal-epidermal attachment. In 2010 Elisabeth’s work continues to focus on the role of
integrins in development and the comprehension of the integrin signaling pathway
in vivo, using in-utero electroporation, while
equally studying the mechanisms of epithelium organization and maintenance of their
integrity in skin and intestine. n
2
11
highlights
• Cell differentiation and plasticity: We identified the glial lineages and the glial determinant,
Glide/Gcm transcription factor, necessary to
induce gliogenesis and sufficient to reprogram
cells towards the glial fate. We determined Gcm
molecular cascade and provided evidence for
evolutionary conservation.
1
probing complexity
A major challenge in developmental biology is to understand how cell diversity is generated and how cells interact to build the sophisticated metazoan architecture. In
humans, defects in such events lead to severe pathologies,
from mental retardation to cancer.
Evolutionary conservation, sophisticated genetics and
simple organization make the fly an ideal tool to study
these events in vivo and in vitro, at cellular resolution. The
nervous system constitutes one of the most complex tissues, made of neurons and glia of different types. These
cells arise from multipotent precursors or stem cells. The
analysis of the signals controlling stem cell differentiation
and reprogramming has recently drawn much attention,
due to potential medical applications.
Our goal is to study the molecular and the epigenetic
events controlling cell differentiation and reprogramming.
During development, many cells move as cohorts to attain
their final destination and shape both tissues and organs.
Distinct homeostatic cell interactions control directionality, coordination and integrity of the migratory unit.
This dynamic event can hardly be tackled in vivo in large
animals. We have developed a simple model to analyze
the cellular and molecular features of this collective behavior.<
shaping the future
Cellular and molecular mechanisms
of nervous system differentiation
The integration of complex molecular cascades and cell
interactions secures the differentiation of the diverse cell
types and tissues that compose a multicellular organism.
Modern biology tackles the molecular, epigenetic and
cellular mechanisms underlying these events with
unprecedented resolution in space and time.
We are convinced that understanding how cells enter a
specific differentiative pathway and attain their appropriate
position requires a multidisciplinary approach that straddles
genetics, molecular and cellular biology, imaging and
informatics.
Our in vivo and in vitro studies will also address the
conservation of these pathways throughout evolution.
<
• Collective cell migration: We identified a glial
migratory chain in the fly nervous system and
specific cell interactions required for collective
migration by genetic, ablation and time-lapse
approaches. Glia interacts with the neuronal
substrate to gain directionality. Also, glial cells at
the chain tip (pioneers) explore the environment
and trigger the movement of following glia. In
addition, homotypic interactions within the migratory unit control the extent of migration and
chain integrity.
Angela Giangrande
Drosophila’s brain
• An animal model for human pathologies: We characterized a molecular pathway linked to the Fragile X Mental
Retardation Protein, the mutation of which induces most
frequent cognitive defects in humans. We also created a
transgenic model for a severe and frequent form of human
retinal degeneration (Retinitis Pigmentosa). n
Su-chun Ho M, Chen H, Chen M, Jacques C, Giangrande A, and Chien C-T. Gcm protein degradation
mediated by F-box E3 ligases suppresses proliferation of glial progenitors.
PNAS. 106:6778-83. (2009).
1- Pupal eye triple
labeled with glia (red),
photoreceptor (green) and
axonal (blue) markers.
2- Neural and glial
labeling on pupal wing.
Aigouy B, Lepelletier L, and Giangrande A. Chain
migration requires pioneer cells.
J Neurosci. 28:11635-41. (2008).
Soustelle L, Trousse F, Jacques C, Ceron J, Cochard
P, Soula C, and Giangrande A.
Neurogenic role of Gcm transcription factors is
conserved in chicken spinal cord.
Development. 134:625-634. (2007).
De Iaco R, Soustelle L, Kammerer M, Sorrentino S,
Jacques C, Giangrande A. Huckebein mediated autoregulation of Glide/ Gcm triggers glia specification.
EMBO J. 25:244-254. (2006).
2
After studying thalassemia at Bari University in Italy, Angela Giangrande joined G.
Richards’ team in 1984 and obtained her
PhD in 1988 on transcription regulation in
Drosophila. During her postdoc research
with J. Palka at the University of Washington
(Seattle) she began a long fascination with
the development of the Drosophila nervous
system where she discovered the origin of
adult peripheral glial cells.
Since 1992, she has led a team on nervous
system differentiation and has studied molecular and cellular associated mechanisms.
She uses the Drosophila as a model to study
conserved mechanisms and molecules. On
glial differentiation, her work led to the identification and characterization of the glial determinant Glide/Gcm (1996). She now focuses
on the mechanisms controlling cell plasticity
and collective cell migration. Her research on
human disease modeling led to the discovery of the link between the Fragile X Mental Retardation protein and actin remodeling
(2003). A transgenic model of retinal degeneration (2005), has also been developed.
Angela coordinated the imaging facility until
2009. n
13
highlights
1
probing complexity
Future strategies for cell replacement therapies and regenerative medicine strongly depend on our knowledge of
the detailed mechanisms that control the differentiation of
multipotent stem cells into highly specialized cells. Along
these lines of research, our goal is to understand how pancreatic and intestinal endocrine cells are generated from
endodermal stem/progenitor cells during embryogenesis
towards adult life. Pancreatic endocrine cells are clustered
in islets within the exocrine tissue and include insulinsecreting beta cells that control glucose homeostasis and
become destroyed in Type-1 diabetes. Intestinal endocrine
cells, also called enteroendocrine cells, are closely related
endocrine cells, found within the intestinal epithelium,
which secrete a variety of hormones promoting pancreatic
insulin secretion to regulate various aspects of digestion.
Particularly, we focus on the role of transcription factors
and signals in the control of cell fate choices and the acquisition of the generic and specific properties of islet and
enteroendocrine cell during organogenesis. We hope that
our studies will contribute to the development of a cell
based therapy in diabetes, as well as to understand the
mechanisms underlying the pathophysiology of islet and
enteroendocrine hormone failure in the human.<
• Cell fate choice: We made the seminal discovery that the transcription factor Neurogenin3
(Ngn3) is the master gene controlling endocrine
cell fate choices both in the embryonic pancreas
and intestine. Mice without Ngn3 lack islet and
enteroendocrine cells are diabetic and die postnatally.
• Differentiation Programme: We determined
the transcriptome of islet progenitors leading to
the identification of Insm1 and Rfx6 transcription factors as two downstream effectors of Ngn3
endocrinogenic function. We reported for the
first time that Rfx6 is essential for proper islet cell
development.
• Beta cell neogenesis: We contributed to the demonstration that new beta cells can arise, de novo,
from progenitor cells in the injured adult mouse
pancreas.
Mellitzer, G., Beucher, A., Lobstein, V., Michel, P.,
Robine S., Kedinger, M., and Gradwohl, G. Loss of enteroendocrine cells in mice alters lipid absorption and
glucose homeostasis, and impairs postnatal survival.
Journal of Clinical Investigation. 120:1708-21. (2010).
shaping the future
Control of endocrine cell differentiation
in the pancreas and intestine
An important bottleneck in the generation of beta cells
from human ES cells is the inability to obtain functional,
glucose responsive, insulin-secreting beta cells in vitro. For
this reason, our current studies emphasize unappreciated
signaling pathways and mechanisms of islet progenitor cell
maturation. We also generated mouse models mimicking
human beta cell deficiency to determine whether mouse
and human beta cells differentiate according to similar
genetic pathways and to explore mechanisms of beta cell
regeneration in the adult pancreas.
In the intestine we further investigate the role of
enteroendocrine cells/hormones in the maintenance of the
homeostasis of the intestinal epithelium and in the control of
nutrient absorption and energy metabolism.<
Gérard Gradwohl
Mechanisms
of stem/progenitor cells
differentiation
• Signals: We demonstrated that retinoic acid signaling
is required for the normal development of the dorsal pancreas.
• Enteroendocrine cells: We generated the first mouse model with a specific ablation of enteroendocrine cells and
discovered that enteroendocrine cells/hormones are essential for life and control intestinal crypt cell homeostasis as
well as lipid absorption. n
Soyer, J., Flasse, L., Raffelsberger, W., Beucher, A.,
Orvain, C., Peers, B., Ravassard, P., Vermot, J., Voz, M.
L., Mellitzer, G. and Gradwohl, G. Rfx6 is an Ngn3-dependent winged helix transcription factor required for
pancreatic islet cell development.
Development 137:203-212. (2010).
1- Enteroendocrine progenitor cells
(Ngn3-eYFP in yellow) in intestinal
crypts of adult mouse small intestine.
2- Insulin-producing beta cells (red) in
the adult mouse pancreas express Rfx6
transcription factor (green nuclei).
Xu,X., D’Hoker,J., Stange,G., Bonne,S., De Leu,N.,
Xiao,X., Van de,C.M., Mellitzer,G., Ling,Z., Pipeleers,D.,
Bouwens,L., Scharfmann,R., Gradwohl,G., and
Heimberg,H. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.
Cell. 132:197-207. (2008).
Martin,M., Gallego-Llamas,J., Ribes,V., Kedinger,M.,
Niederreither,K., Chambon,P., Dolle,P., and Gradwohl,G.
Dorsal pancreas agenesis in retinoic acid-deficient
Raldh2 mutant mice. Dev. Biol. 284:399-411. (2005).
As a PhD student at the IGBMC (Strasbourg),
working on DNA repair, Gérard Gradwohl
showed that the Zinc-finger domains of Poly
(ADP-ribose) polymerase detect DNA strand
breaks (1990). He then became interested in
development biology and relocated as postdoc to the Mount Sinai Hospital (Toronto,
Canada) where he studied, in 1992, TIE2, a
tyrosine kinase receptor that controls angiogenesis in the mouse embryo. Gérard then
joined the team of Francois Guillemot at the
IGBMC on the role of bHLH transcription factors in neurogenesis.
In 2000, he showed that Neurogenin3, one
of the factors studied, was also key for pancreatic beta cell differentiation, a discovery
which promoted the creation of his Inserm
team at Hautepierre Hospital (Strasbourg).
His group then determined that neurogenin3 also controls endocrine fate decision in
intestinal stem cells. In 2008, he joined the
IGBMC to develop his research on the regulation of endocrine cell differentiation in the
pancreas and intestine. n
2
15
highlights
1
probing complexity
Our focus is to understand how neurons are specified within uniform fields of cells. We use the power of Drosophila genetics to address this question. The regulation of
the two key proneural genes Achaete and Scute provide the
identity and the position of most of the sensory organs
within the peripheral nervous system. Achaete and Scute
encode bHLH transcription factors, which, together with
the Zn-finger transcription factor GFI/Senseless, confer
the potential to develop a neural fate to cells. The general
architecture of the peripheral nervous system, also called
prepattern, is controlled by specific transcription factors.
These bind to enhancers common to both Achaete and
Scute which in turn promote proneural expression in small
fields of cells, the proneural clusters, at reproducible antero-posterior and dorso-lateral coordinates. The spacing
between neuron precursors is achieved by a mechanism
known as lateral inhibition, which involves the Notch receptor and its ligand Delta. We recently showed that several decisions mediated by Notch and Delta are fine-tuned
and controlled by a common set of microRNAs. Collectively, these mechanisms define the positions and identities
of each sensory organ; similar mechanisms are conserved
in human haematopoiesis and might be at play in the etiology of T-ALL leukemia. <
• Our genetic screens led us to characterize several zinc finger-containing transcription factors
(the GATA factor Pannier, the FOG homologue
Ushaped, the LIM proteins Islet and dLMO)
that together define the prepattern for the median thorax.
• We have highlighted the importance of the
Ldb homologue Chip in stabilizing enhancerpromoter communications during Achaete/Scute
transcription. Moreover, we showed that dLMO
acts as an activator, while Islet and Ushaped behave as negative regulators, of the Pannier/Chipdependent Achaete/Scute expression. Both Ushaped and Pannier recruit the dCtBP protein and
its partner HDAC1 in a repressive mechanism
involving alteration of local chromatin structure,
while Islet repression seems to mediate competition for Chip.
Heitzler P. Biodiversity and non canonical Notch signaling. In «Notch signaling». (R. Kopan, Ed),Elsevier
Inc., San Diego. Current Topics in Developmental
Biology. 92:427-451. (2010).
shaping the future
Genetic and molecular analysis of early
neurogenesis in Drosophila melanogaster
The regulation of Achaete/Scute by Islet seems to depend
on the specific enhancer context. In order to clarify how enhancer position and context can lead to different outcomes,
we have developed sensors in Achaete 5’UTR that allow us
to measure in vivo variations in enhancer-promoter co-operations. We have also identified a novel enhancer, Scutellar,
that appears to mediate such variation in Achaetae/Scute
expression
Currently, we are exploring three mir-9 and three mir-9* products as regulators of a clock-pulsed feedback loop of Notch.
With the use of new tools, we are performing a unique genetic analysis to reveal the individual contribution and expression patterns for each mir hairpin. Similar mechanisms
may be involved in acute leukemia and several non-Hodgkins
lymphomas in human. We will perform microarray assays to
check whether specific miRNA may influence early LMO2- or
Notch-dependent steps of T-cell differentiation in mouse.<
Pascal Heitzler
Formal genetics as a vocation
• The main dLMO isoform, named dLMO-PA, controls
both neurogenesis and wing development. dLMO is homologous to the leukaemogenic factor LMO2 that is
found in similar transcription complexes in human. We
found that an ancient family of miRNAs (mir-9) regulates
dLMO abundance, and in turn controls neurogenesis in
Drosophila. Thus, as for LMO2, dLMO stoichiometry is
critical in vivo. n
Biryukova I, Asmar J, Abdesselem H & Heitzler P.
Drosophila mir-9a regulates wing development via
fine-tuning of LIM only factor, dLMO.
Dev Biol. 327:487-496. (2009).
Biryukova I & Heitzler P. Drosophila C-terminal
binding protein, dCtBP is required for sensory organ
development and sharpens a proneural transcriptional activity of GATA factor, Pnr.
Dev Biol. 323:64-75. (2008).
1- MicroRNA expression in
imaginal disc.
2- MicroRNA expression
in brain.
Pascal Heitzler developed very early on an
interest for genetics. His encounter with Pat
Simpson in 1985 confirmed his vocation and
he joined her team for his PhD on the analysis
of developmental genetics on sensory organ
patterns Drosophila (1993). Together they
were the first to reveal the role of Notch/Delta
as receptor/ligand during lateral inhibition.
In 1994, he obtained a post-doc position at
the IGBMC and revealed a feedback loop
mechanism in Notch-Delta signaling. He
then discovered a genetic network, including
GATA, FOG, LIM-HD, Ldb, LMO, SWI/SNF
transcription factors which are involved
in sensory bristle prepatterning. In 2001,
he became a team leader and described
the role of Chip in proneural enhancerpromoter communications, as well as a new
non-canonical Notch pathway. His recent
projects focus on miRNAs that control all the
described processes. n
Asmar J, Biryukova I & Heitzler P. Drosophila dLMOPA isoform acts as an early activator of achaete/
scute proneural expression.
Dev Biol. 316:487-497. (2008).
Biryukova I & Heitzler P. The Drosophila LIM-Homeodomain Islet protein antagonizes proneural cell
specification in the peripheral nervous system.
Dev Biol. 288:559-570. (2005).
2
17
highlights
1
probing complexity
How differentiated cells can change their identity is a fascinating question in biology and has implications for the development of regenerative medicine strategies. Numerous examples
of cellular plasticity in physiological, experimental and pathological settings exist, but how a differentiated cell can change its
identity remains unknown. Our research tackles this important
question by employing a powerful and innovative model, the
nematode C. elegans.
We study in vivo cell reprogramming events at the single cell
level. Specifically, we focus on a differentiated rectal cell (named Y) that during normal development changes its identity
into a motoneuron (named PDA). We notably investigate the
cellular and molecular events underlying Y-to -PDA cellular
reprogramming. Our system also allows us to identify the molecular players and to dissect the cellular requirements during
cell type conversion in vivo. Comparing different cell plasticity
events, we are assessing what key aspects have been conserved
in cell reprogramming.
Our integrated approach will contribute to unraveling the key
mechanisms that allow a differentiated cell to become plastic
and change its identity. This knowledge has significant therapeutic implications, as it will further our understanding as to
how certain cancers arise, and will improve our ability to reprogram cells for regenerative medicine purposes. <
• Cellular potential: We have found that a pulse
of Notch signal is necessary for the Y cell to acquire the competence to switch identity.
• Direct cell type conversion occurs in vivo
through distinct intermediate cellular steps, not
via a mixed cellular identity. Remarkably, Y-toPDA conversion, which occurs in the absence of
cell division, involves as a first step the complete
erasure of the initial identity. Importantly, this
dedifferentiated state has limited cellular potential. This suggests that unlike reprogramming
induced in vitro, natural in vivo reprogramming
is much more constrained.
• Technical development: We have developed
Deep Mapping, an innovative method using
next generation sequencing, which allows mutation identification without any prior SNP
Zuryn S., Le Gras S., Jamet K. and Jarriault S. Deep
Mapping: A novel mutagen-based method for direct
mapping and mutation identification using deep
sequencing, in Press Genetics. (2010).
shaping the future
In vivo analysis of cellular plasticity
in C. elegans
The aim of our work is to systematically address the cellular
and molecular mechanisms that allow a differentiated cell
to be reprogrammed and change identity. Such knowledge
has profound implications for the elaboration of therapeutic strategies, both in cancerology and in cellular therapy.
Many technical obstacles remain in complex organisms to
address these questions in vivo, in particular because it is
virtually impossible to track cells as they get reprogrammed
in mammals.
Our novel experimental model, combined with integrated
molecular and cellular in vivo approaches allows us to bypass these limitations and bring new insights into cellular
plasticity. We will focus on the mechanisms that make a
specific cell, rather than its neighbors, competent to change
identity and the cellular mechanisms that are used to allow
its conversion. The comparison of the mechanisms used in
different direct reprogramming events will be key for our
understanding of cellular plasticity in vivo.
knowledge. Deep Mapping is a powerful, yet a conceptually simple strategy that is easy to apply to different model organisms.
• Impact of cell division on the cellular potential: Comparison of reprogramming events in C. elegans suggests that
different cellular strategies are used to erase the initial identity: retraction from the tissue, which resembles an EMT,
or asymmetric cell division. n
Jarriault S. LIN-12/Notch signaling: Induction, lateral
specification and interaction with the EGF/Ras pathway. Handbook of Cell Signaling 3rd Edition (Eds.
R.A. Bradshaw and E.A. Dennis).
Elsevier Academic Press. :1891-1895. (2009).
1- Visualization of the adherens junctions that shape the posterior of the
worm, including the rectal area.
2- Electron microscopy picture of the
rectal area of a young C. elegans larva,
showing Y cell epithelial cell. Ventral is
to the bottom.
Jarriault S.*, Schwab Y. & Greenwald I. A C. elegans
model for epithelial-neuronal transdifferentiation.
PNAS, 105(10) : 3790-5 *, corresponding author.
5/3/08 « Must Read », « Top 10 Developmental
Biology Papers » of Faculty 1000. (2008).
Jarriault S. and Greenwald I. Functional interchangeability of ADM-4/Tace and SUP-17/Kuzbanian in C. elegans. Developmental Biology. 287(1):1-10 (2005).
<
Sophie Jarriault
Cellular plasticity and
reprogramming in C. elegans
Sophie Jarriault obtained her PhD in Alain
Israël’s laboratory at the Pasteur Institute
(Paris) where she worked on the transduction of the Notch signal in mammals. In 1998,
her research led to an original model for signal transduction involving cleavage of the
Notch1 transmembrane receptor and release
of the intracellular part. She did her postdoc research at Columbia University (New
York), where she worked with Iva Greenwald
on vulva organogenesis in C. elegans. She
notably, involved the COREST corepressor
and the LSD1 demethylase in downstream
modulation of Notch-mediated target genes
expression.
In 2006, she was awarded the Young Investigator Starting Grant (ATIP-CNRS) as well as
other grants from the ARC, FRM and AFM to
start her own team at IGBMC. Sophie chose
to focus her research on cellular plasticity. At
Present, her team works on the mechanisms
of cellular reprogramming in C. elegans, and
has established the worm as a powerful animal model to study such processes in a physiological context. n
2
19
highlights
• Cell polarity: We previously analysed genes that
maintain epithelial polarity and adherens junction integrity.
• Forces in morphogenesis: We identified several
pathways that control myosin II activity and
found that myosin II is mainly active in a subset
of cells. Modelling in collaboration with physicists has confirmed our genetic data.
1
probing complexity
Our team’s research is based on the interface of cell and developmental biology, focusing on epithelial tissues, which
form the architecture of most of our organs. These highly
polarized cells that have specific junctional complexes,
play an essential role during embryonic morphogenesis, as
well as later on in physiology.
The goal of our research is to explain how embryos form
and grow to generate organs with different properties and
shapes. We are dissecting the processes that create a lumen,
secrete specific proteins to distinct surfaces, or bring cell
shape changes. Many organs include several cell types of
epithelial and non-epithelial origins; an important focus of
our studies is to understand how these cells interact with
each other to achieve higher order tissue morphogenesis.
In parallel, we intend to use the knowledge gained from
studies in embryos to reveal the causes of pathologies involving structures, such as the hemidesmosome, that are
present in C. elegans and mammals.
We are mainly using the model C. elegans, combining
molecular genetics and modern imaging methods to
capitalize on the speed of development and simplicity of
this system. <
shaping the future
Forces and signals
in tissue morphogenesis
Today, in connection with the analysis of cell shape changes
and secretion, my lab is focusing on the input of physical
forces in morphogenesis. My view is that physics is at
the crossroads of cell and developmental biology, and will
provide major input to interpret key biological processes. It
offers very important perspectives for the decade to come.
More generally, we are reaching a point where quantitative
analysis and modelling is becoming essential in biology.
To accomplish this, in the coming years, we will progress
along two axes:
● Analyze the role of forces in epithelial morphogenesis,
including their input on trafficking
● Study how osmotic pressure affects membrane tension
and lumen shape.<
Michel Labouesse
• Hemidesmosomes (HDs): We have contributed to define the nature of HD-like junctions
between the epidermis and the ECM and revealed how the spectraplakin VAB-10 maintains
epidermal integrity against mechanical stress
during morphogenesis. More recently, we could
identify proteins that promote HD biogenesis
and found that HDs provide a platform for mechanotransduction during morphogenesis.
Through epithelial cell
differentiation
• Trafficking: We characterized the first transmembrane
complex acting in apical trafficking. By doing so, we
showed that apical secretion of some protein cargos involves the release of exosomes from multivesicular bodies,
which is mediated by the V0 sector of the V-ATPase.
Zahreddine H*, Zhang H*, Diogon M, Nagamatsu Y,
Labouesse M. CRT-1/calreticulin and the E3-ligase EEL-1/
HUWE1 control hemidesmosome maturation in C.
elegans development.
Curr. Biol. 20:322-327. (* co-first) (2010).
• New technique: We designed a protocol to easily bridge
time-lapse imaging with electron microscopy (CLEM). n
Gally C, Wissler F, Zahreddine H, Quintin S, Landmann
F, Labouesse M. Myosin II regulation during C. elegans
embryonic elongation: LET-502/ROCK, MRCK-1 and PAK1, three kinases with different roles.
Development. 136:3109-19. (Issue cover). (2009).
1- Closing the gap between fast
fluorescence videomicroscopy and
high resolution electron microscopy
through Correlative Light and
Electron Microscopy.
2- A 4-colour view of the main C.
elegans hemidesmosome components and underlying muscles.
Ciarletta, P., Ben Amar, M., and Labouesse, M. Continuum model of epithelial morphogenesis during C.
elegans embryonic elongation.
Philos Transact A Math Phys Eng Sci. 367:3379-400.
(2009).
Liégeois, S., Benedetto, A,, Garnier, J.M., Schwab, Y. and
Labouesse, M. The V0 ATPase mediates apical secretion
of Hedgehog-related proteins through exosomes.
J. Cell Biol. 173:949-961. (rated Must Read by F1000).
(2006).
Having an engineering degree in maths
and physics from Ecole Polytechnique,
Michel Labouesse began a career in biology
and obtained his PhD in genetics in Piotr
Slonimski’s laboratory (Gif-sur-Yvette, 1983).
His work dealt with the control of
mitochondrial gene expression by nuclear
genes. Inspired by Sydney Brenner’s work
on the nematode C. elegans, he decided
to switch to this model in 1989 during his
postdoc at MIT.
Supervised by H. Robert Horvitz, he was
initially interested in understanding how two
cells become different during asymmetric
cell division. The Zn-finger transcription
factor LIN-26 that characterized turned out
to be essential for the differentiation of
the entire skin. Michel began his research
at IGBMC in 1992 and went on to work
on epithelial morphogenesis. Today, he
leads the Development and Stem Cells
Programme. n
2
21
highlights
1
probing complexity
Retinoic acid (RA), the biologically active metabolite of vitamin A, exerts a wide range of cellular effects by regulating
proliferation, differentiation and apoptosis. At the cellular
level, the action of RA is controlled through the modulated
expression of cellular enzymes producing or degrading RA,
retinaldehyde dehydrogenases (RALDH) or cytochrome
P450 hydroxylases (CYP26), respectively. Then, acting in
an hormone-like manner, RA binds to nuclear receptors
(RAR) that function as transcriptional regulators through
controlling, usually in the form of heterodimers with rexinoid receptors (RXR), the expression of RA target genes.
Among the various tissues whose physiology depends upon
vitamin A action, the seminiferous epithelium of the testis
represents the most remarkable paradigm to investigate the
pleiotropic effects of RA in vivo, as it integrates the problematic of stem cell renewal, cell proliferation, switching
from mitotic to meiotic cell division, programmed cell
death and paracrine signaling. Using a combination of
innovative genetic, pharmacological and molecular approaches in the mouse, we are studying the cellular and
molecular mechanisms that underlie the capabilities of RA
to promote spermatogonia differentiation and beyond the
differentiation of normal stem cells in vivo.<
• Two distinct, sequential, sources of RA involved
in spermatogonia differentiation. RA synthesized
by somatic Sertoli cells is indispensable only during the prepubertal wave of spermatogenesis.
The subsequent differentiation of spermatogonia requires RA synthesized by their progenies,
the meiotic spermatocytes, a mechanism which
might be instrumental to the perpetuation of the
spermatogenetic cycle.
• A catabolic barrier protects spermatogonia from
untimely differentiation. The peritubular myoid
cells that surround the seminiferous epithelium
isolate spermatogonia from extratubular sources
of RA through synthesizing the RA-degrading
enzymes, CYP26.
• A model of non-canonical mechanism of action
for RAR. As the pathological phenotypes resul-
Mascrez B, Ghyselinck NB, Chambon P, Mark M. A
transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.
Proc. Natl. Acad. Sci. USA. 106:4272-4277. (2009).
shaping the future
Retinoic acid signalling pathways driving stem
spermatogonia ontogenesis and differentiation
The seminiferous epithelium comprises somatic,
supporting, Sertoli cells that contribute to the niche
environment directing the fate of spermatogonia.
Outside their niche, spermatogonia can become
multipotent and therefore represent possible tools
for cellular therapy.
We propose to identify the genetic networks and
to characterize the molecular mechanisms through
which RA, notably in Sertoli cells, controls spermatogonia proliferation and differentiation. Our preliminary data indicate that expression of the few
genes known to be involved in stem spermatogonia
homeostasis is not altered upon impairment of RA
function. Thus, RA acts on yet uncovered genetic
cascades, the understanding of which will open
new perspectives on stem cells with promising therapeutic potential.<
Norbert Ghyselinck
At the face of Molecular
Genetics and Developmental
Biology
ting from the ablation of RAR and of RXR in Sertoli cells
are really different, the canonic RAR:RXR heterodimers
do not operate in these cells. This probably also applies to
spermatogonia.
• A novel switch which controls the choice between mitosis
and meiosis. STRA8 protein is involved in the process that
leads to stable commitment of differentiated spermatogonia to the meiotic cell cycle. n
Mark M, Jacobs H, Oulad-Abdelghani M, Dennefeld C,
Féret B, Vernet N, Codreanu CA, Chambon P, Ghyselinck NB. STRA8-deficient spermatocytes initiate,
but fail to complete, meiosis and undergo premature
chromosome condensation.
J. Cell Sci. 121:3233-3242. (2008).
1- Immunostaining of spread
nuclei to visualize chromosomes
during meiosis
2- Histological section showing
pathological accumulation
of lipids in the seminiferous
epithelium
Vernet N, Dennefeld C, Guillou F, Chambon P, Ghyselinck NB, Mark M. Prepubertal testis development
relies on retinoic acid but not rexinoid receptors in
Sertoli cells. EMBO J. 25:5816-5825. (2006).
Mark M, Ghyselinck NB, Chambon P. Function of
retinoid nuclear receptors: lessons from genetic and
pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis.
Annu. Rev. Pharmacol. Toxicol. 46:451-480. (2006).
Manuel Mark
Mark Manuel obtained an MD degree from
Strasbourg University and defended his PhD
in 1988 on extracellular matrix functions
during embryonic development. After
joining Pierre Chambon’s team in 1992 he
became involved in the phenotypic analysis
of Hox gene mutant mice. In 1993 he initiated
collaboration with Norbert Ghyselinck who
was also a member of Chambon’s team.
Norbert Ghyselinck received his PhD in
1991 from Clermont-Ferrand University. His
research focused on the regulation of gene
expression by nuclear receptors. In 2004 he
was appointed a Research Director of the
CNRS.
Together, Mark and Ghyselinck formed a
team at IGBMC to decipher retinoic acid
signaling pathways during differentiation
of male stem cells. In 2006, they brought to
light non-canonic mechanisms of actions for
retinoic acid receptors in vivo. n
2
23
highlights
1
probing complexity
We are interested in the mechanisms controlling the formation of the body of vertebrates during embryogenesis.
In particular, we have been focusing on the process of axis
elongation and on segmentation whereby a periodic series of anatomical structures such as vertebrae are formed
during organogenesis. Our work relies on developmental
biology studies in chicken, mouse and zebrafish embryos
combining genetic approaches with genomic strategies
such as transcriptomics or high throughput sequencing
and bioinformatics as well as sophisticated in vivo imaging. Our goal is to understand the basic principles underlying these morphogenetic processes. We are actively collaborating with physicists and mathematicians to attempt
to model these complex molecular and cellular processes
in the embryo.
Equally we are interested in the clinical relevance of these
findings and are exploring the molecular basis of spine
patterning defects such as scoliosis in humans. Lastly, we
are moving into the field of regenerative medicine, translating our understanding of differentiation of the muscle
and vertebral lineages into in vitro strategies to differentiate mouse and human embryonic or reprogrammed stem
cells for cellular therapies of degenerative diseases such as
Duchenne muscular dystrophy. <
• Segmentation clock : We have identified a molecular oscillator associated with the process of
rhythmic production of vertebral precursors
in the embryo. The pulsatile signal generated
by the oscillator travels progressively along the
embryo thus generating the spatial periodicity
of the future vertebrae. This led us to propose a
comprehensive paradigm accounting for vertebrate segmentation.
• Axis elongation : We have shown the role of
Hox genes in the collinear control of mesodermal cell ingression and proposed a mechanism
akin to diffusion involving a gradient of random
cell motility to explain the striking terminal
elongation process resulting in body formation
in the embryo.
• Bilateral symmetry : We have demonstrated that
a novel pathway downstream of retinoic acid is
Bénazéraf, B., Francois, P., Baker, R.E., Denans, N.,
Little, C.D., & Pourquié, O., A random cell motility
gradient downstream of FGF controls elongation of
an amniote embryo Nature. in press (2010).
shaping the future
Development of muscle
and vertebrae
My lab is now trying to understand the mechanisms
controlling axis formation and patterning at the genomic
level.
We have set out to identify the gene regulatory networks
involved in these processes focusing on the molecular
basis of the oscillator controlling segment production
and on the control of differentiation of the muscle and
vertebral lineages. Our work now relies more and more on
quantitative approaches and modeling at the interface with
physics.
In parallel, we are developing in vitro systems of these
processes using embryonic or reprogrammed stem cells,
with the goal of using these systems to shape strategies
for therapeutical approaches of diseases of the musculoskeletal axis.<
Olivier Pourquié
All about embryo patterning
required to buffer the desynchronizing effect of the leftright machinery which controls the asymmetrical development of organs such as heart or liver. This mechanism
maintains the bilateral symmetry of cervical somites.
• Segment number : We have identified a mechanism involved in the control of vertebral number and have demonstrated that in snakes, acceleration of the segmentation clock accounts for the increase in vertebral count. n
Vilhais-Neto, G.C., Maruhashi, M., Smith, K.T.,
Vasseur-Cognet, M., Peterson, A.S., Workman, J.L.,
& Pourquie, O., Rere controls retinoic acid signalling
and somite bilateral symmetry.
Nature. 463(7283):953-957 (2010).
1- Somite organization highlighting
the actin-rich apical side of epithelial
cells (green), nucleus (blue), basal side
(red).
2- Segmental gene expression in
embryo. HN-Cadherin (green), actin
(red), nucleus (blue). Dorsal view.
Gomez C, Ozbudak EM, Wunderlich J, Baumann D,
Lewis J & Pourquié O. (2008). Control of Segment
number in vertebrate embryos.
Nature. 454(7202):335-9. (2008).
Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M.,
Chen, J., Mushegian, A., & Pourquie, O., A complex
oscillating network of signaling genes underlies the
mouse segmentation clock.
Science. 314(5805):1595-1598 (2006).
Olivier Pourquié graduated as an engineer
from the National Institute of Agronomy and
completed his PhD and postdoc work in developmental biology with Nicole le Douarin
at the College de France.
In 1996, he became an independent group
leader at the Institut de Biologie du Développement de Marseille (IDBM). There, he
published the first evidence of a molecular
oscillator which controls segmentation of
the vertebral precursors, the segmentation
clock. This discovery was acknowledged as
one of the 24 milestones in developmental
biology over the past 100 years by the magazine Nature.
In 2002, he joined the Stowers Institute for
Medical Research (US) and became a Howard Hughes Medical Institute Investigator in 2005. In 2009, he returned to France
and became the director of the IGBMC. His
research is focused on the development of
muscle and vertebrae, using in vivo strategies such as mouse genetics and microsurgery or in vitro approaches based on embryonic stem cells. n
2
25
highlights
• Collective effects in vitro: We showed an instability of molecular motors by developing a new
acto-myosin motility assay. The filaments go
spontaneously back and forth, which suggests
an oscillatory mechanism at play in cells.
• Mechanosensing in cell adhesion: We demonstrated that focal contacts and cell-cell contacts are
undergoing elongation upon force application.
This reinforcement mechanism explains key aspects of cell motility and tissue organisation.
1
probing complexity
Cells are traditionally viewed as a soup of chemical reactions. However cell shape is also the result of self-assembly
phenomena; the physical laws of matter provide the appropriate framework for understanding shapes of cells and
tissues. Within the cells, the cytoskeleton dynamics and
its associated Rho pathways give the proper unit for understanding cell motility, cell division and cell shapes within tissues. We use interdisciplinary approaches to address
these phenomena in cell culture. The physical framework
is inspired from soft matter physics. The biological side
is adapted from cell biology for changing specifically cell
shapes with cytoskeleton drugs, genetic modifications,
and mechanical constraints. The chemical part consists
in designing new agents for altering cell motility and cell
division. In the long term, our research may provide new
ideas for understanding cancer.
Being interdisciplinary in nature, our group is located both
at The Science and Supramolecular Engineering Institute
in Strasbourg for the physical/chemical themes as well as
at the IGBMC for those of cell biology. We use classical
cell lines for fibroblasts and epithelium, along with fission
yeast as a model system for cytokinesis. Microfabrication
plays a key role for our measurements of forces, as well as
for ordering cells in our experiments.<
• Soft Matter Physics for Cells: We developed
quantitative models for explaining the shapes of
adhesive contacts and the shapes of yeast cells.
The geometrical relations are derived from physical laws demonstrated in soft matter systems.
shaping the future
Laboratory of
Cell Physics
Our research is articulated around three axes :
● Rectification of individual cells’ motion : By using surface
patterning, we are seeking to show that the directed motion
of cells can be a physical mechanism with no chemical gradients. Some synthetic molecules targeted against the actin
cytoskeleton are also tested in collaboration with the laboratory of J.-M. Lehn at ISIS.
● Dynamics of monolayer : We are studying the evolution
of cells monolayer under the microscope and in silico; we
translate images of contacts into local constraints in order
to explain and predict the changes in local and global shapes
of cells monolayers. Extensions for this project address the
distributions of constraints within developing embryos with
several groups at IGBMC, in particular the teams of O. Pourquié and M. Labouesse.
● Cell division : We are characterizing the closure of the cytokinetic ring in a chemical physics way by using a new method
of observation, combining microfabrication, genetics, and
optical observations. A technology transfer based on our
new method is being developed for a new high-throughput
screening device for anti-cancer drugs.<
• The cytokinetic ring closure: By developing a new approach, we outlined a mechanism for explaining the closure of the cytokinetic ring in fission yeast. The action of
molecular motors promotes the ring closure. n
Riveline D., P. Nurse, Injecting yeast,
Nature Methods. 6:513. (2009).
Riveline D. Explaining lengths and shapes of yeast by
scaling arguments.
PLoS One. 4(7):e6205. (2009).
Brevier J, Montero D, Svitkina T, Riveline D.
The asymmetric self-assembly mechanism of adherens junctions: a cellular push-pull unit.
Phys Biol. 5(1):016005. (2008).
Brevier J., M. Vallade, D. Riveline, Force-extension
relationship of cell-cell contacts,
Phys. Rev. Lett. 98:268101. (2007)
2
1- Reinforcement in cells. Cells
probe their environment by
pulling on adhesion areas.
2- Microfabrication and Biology.
By imposing the location of
individual yeast cells, we can study
self-assembly mechanisms and
develop new methods such as the
first yeast injection shown here.
Daniel Riveline
Physics to explain roles of
molecular motors in biology
Daniel Riveline graduated with a master’s
degree in physics and then received a PhD
at the Curie Institute (Paris). He focused on
actin-myosin molecular motors with J. Prost
and A. Ott and in 1997 he revealed the oscillatory nature of these motors. Next he obtained a post-doc position at the Weizmann
Institute (Israel) with A. Bershadsky where
he was trained in cellular biology and studied cell adherence to the extracellular matrix.
In 1999, he created his own group in cellular
adhesion and the structure of chromosomes.
Demonstrating cell mechanosensory mechanisms for focal contacts and intercellular
contacts. A sabbatical in P. Nurse’s team at
the Rockefeller University followed where
he focused on cytokinetic ring closure and
developed a new method to observe this
process.
In 2009, he created the Laboratory of Cell
Physics, a joint laboratory between the Institut de science d’ingénierie supramoléculaires (ISIS) and the IGBMC. n
27
highlights
• Reprogramming:
In an effort to delve into the mechanisms governing epigenetic reprogramming, we have identified new histone modifications and uncovered
putative roles for histone variants in this process.
shaping the future
Epigenetics and cell fate in early
mammalian development
The proteins that regulate chromatin structure in the early
embryo, or the way in which the chromatin is remodeled
throughout preimplantation development are largely
unknown. Our efforts during the coming years will be
devoted to understand :
● how the structure of the chromatin is established at the
beginning of embryonic development and how it supports
totipotency.
● which players are involved in chromatin remodeling during
early mammalian development.
● the role of these molecules in reprogramming and in
formation of the pluripotent compartment of the inner cell
mass.<
• Cell fate:
We have determined that by manipulating the
epigenetic information of a cell we can regulate
its fate. We also revealed that histone modifications, in particular arginine methylation, can regulate pluripotency in the early mouse embryo.
1
probing complexity
Research in our group focuses on understanding how early
mouse development is regulated by chromatin-mediated
changes in gene regulation, that is, by epigenetic information. In particular, we are interested in understanding how
the transitions in cell potency and cell fate are regulated by
chromatin-mediated processes. We use the mouse embryo
as a model because this is one of the few systems where it
is possible to explore the foundations of totipotency and
differentiation. Indeed, the zygote, which is the product
of fertilization of an oocyte by sperm, has an inherent capacity to form all cell types in an organism. Chromatinmediated changes in gene regulation have to ensure the
plasticity required for undertaking such an essential task
during development.
Our projects will help us to understand how chromatin structure is progressively modified to restrict cell fate
determination with the consequent loss of totipotency.
Our work will also allow new insights in understanding
the biology of the pluripotent stem cells, in particular on
their origin and development. From a broader perspective,
deciphering the basic mechanisms underlying the earliest
steps of mammalian development is essential to understand early aspects of embryonic development, human reproduction and stem cell biology. <
Maria Elena Torres-Padilla
Epigenetics in cellular
differentiation
• Fertility:
By using genetic approaches, we have shown
that a protein related to the TATA-binding
protein, TBP2, is essential for female fertility and oocyte
growth. TBP2 plays its part by regulating the transcriptional Programme of the oocyte as well as chromatin condensation. n
Gazdag E1. Santenard A1. Ziegler-Birling C. Altobelli
G. Poch O. Tora L* Torres-Padilla ME* TBP2 is essential for germ cell development by regulating transcription and chromatin condensation in the oocyte.
Genes and Development. 23(18):2210-23. (2009).
1Equal contribution. *Corresponding authors.
Daujat S, Weiss T, Mohn F, Lange U. C, Ziegler-Birling
C, Zeissler U, Lappe M, Schübeler D, Torres-Padilla
ME, Schneider R. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during
developmental reprogramming.
Nature Structural Molecular Biology; 16(7):777-81.
(2009).
Santenard A. Torres-Padilla ME. Epigenetic reprogramming in mammalian reproduction: contribution from
histone variants. Epigenetics. 4(2):80-84. (2009).
1- Mouse blastocyst a day before implantation. Blue DNA,
yellow cell-cell boundary.
2- Male and female pronuclei
undergoing the first mitosis.
In 2002, Maria Elena Torres-Padilla obtained
her PhD at the Pasteur Institute (Paris) on the
role of the nuclear receptor HNF4 in hepatic
differentiation. Notably, she demonstrated
the role of chromatin factors on the specific
action of splicing variants of HNF4. An interest in chromatin led Marie-Elena to become
focused on its study in early development
transitions. She did post-doctorate research
at the Gurdon Institute (Cambridge University, UK) with Magdalena Zernicka-Goetz in
close collaboration with Tony Kouzarides.
They were able to show that cell fate and
pluripotency are controlled by epigenetic information in the early embryo.
At the end of 2006, Maria Elena Torres-Padilla
joined Laszlo Tora’s team, noted for its biochemical approach on the analysis of transcrition mechanisms, to expand her biochemical skills. At the end of 2008, she created
her own team at the IGBMC on epigenetic
mechanisms in early mouse development. n
2
Torres-Padilla ME. Parfitt D.E. Kouzarides T. and
Zernicka-Goetz M. Histone arginine methylation
regulates pluripotency in the early mouse embryo.
Nature. 445(7124):214-218 (2007).
29
highlights
1
probing complexity
During embryonic development, cells act as force sensors
and can actively trigger physical changes in order to maintain the harmonious body-plan patterning and growth.
Defects in these processes can cause catastrophic developmental abnormalities, in particular in the cardiovascular
system where blood flow is generating shear forces essential for cardiogenesis.
We use live imaging techniques, cell biology and genetic
analysis to study the dynamics and the roles of biological flow during the development of the zebrafish and the
Danio rerio. Our goals are to address the physical stimuli
and the molecular/genetic mechanisms that specify cell
responses to flow forces during embryogenesis. In particular, we are interested in understanding the relationship
between physical forces and tissue organization during endothelium maturation.
Also, we investigate how cells alter and maintain their physical environment to control morphogenesis. To address
this question, we study the activity of beating cilia during
embryogenesis using novel imaging techniques to visualize
and analyze cilia mediated flow. <
• Addressing the dynamics of development: the cardiovascular system is under the influence of complex stimuli generated by flowing blood. We identified the physical stimuli involved in controlling
valvulogenesis during heart development and
found a flow responsive gene linking blood flow
and valve morphogenesis
• Mixing classical approaches in genetics with light
imaging to address cilia activity during development:
We discovered that manipulating cilia dynamics
using mRNA knock down affects inner ear formation. The use of fast imaging uncovered the
mechanism of action of cilia during this process
• Developing approaches to probe flow in vivo: We
used techniques to measure flow and explored
cilia mediated flow in the embryo. In particular, we used fast imaging combined with optical
shaping the future
Mecano-genetic interplays
and embryonic morphogenesis
We aim at investigating the relationship between the
viscous forces generated by blood flow and endothelial
tissue organization. Endothelial cells express different
genes in response to the flow patterns they experience.
Our working hypothesis is that blood flow influences
cardiovascular development by acting on cell identity and
cell motility.
We generated a flow responsive reporter in order to explore
endothelial cell responses to shear forces during embryonic
blood vessel development. This line will allow us to address
precisely the flow-tissue interaction during vascular
development and to address the endothelial cell behavior in
response to flow using live imaging.
We use molecular biology and genetic approaches to
address the gene networks activated by blood flow. <
Fluid dynamics applied to
development
approaches to analyze cilia mediated flow in the left-right
organizer and in the developing inner ear
• Using multidisciplinary approaches to address embryogenesis: In collaboration with physicists, engineers and mathematicians, we proposed new models, approaches and hypothesis to solve problems related to flow. n
Vermot J, Forouhar AS, Liebling M, Wu D, Plummer
D, Gharib M, Fraser SE. Reversing blood flows act
through klf2a to ensure normal valvulogenesis in the
developing heart.
PLoS Biol. e1000246. 7(11) (2009).
1- Intersegmental vessels and
their flow dynamics revealed
by a transgenic line labeling red
blood cell (red) and endothelial
cell response (white).
2- Head vascular network in the
Zebrafish embryo labeled using
the fli:gfp line.
Colantonio JR*, Vermot J*, Wu D, Langenbacher
AD, Fraser S, Chen JN, Hill KL. The dynein regulatory
complex is required for ciliary motility and otolith
biogenesis in the inner ear. (*equal authors).
Nature. 457:205-9. (2009).
Supatto W, E. Fraser S, and Vermot J. An all-optical
method for probing microscopic flows in living tissues. Biophysical J. 95(4):L29-31. (2008).
Vermot J, Fraser SE, Liebling M. Fast fluorescence
microscopy for imaging embryonic development.
HFSP journal. 2:143-155. (2008).
Julien Vermot
In 2003, Julien Vermot completed his PhD
with P. Dollé at the IGBMC in development
biology and genetics. In 2004, he became
a member of O. Pourquié’s team at The
Stowers Institute for Medical Research in
Kansas City, USA to supplement his PhD
work. Next, he joined the group of S. Fraser at the Beckman Imaging Center of the
California Institute of Technology (Pasadena,
USA) as a long term HFSP fellow in 2005.
This experience allowed him to become familiar with a broad range of live imaging
techniques that he would employ to address
the role of cilia driven flow and blood flows
during embryogenesis.
Julian notably demonstrated the role of biological flow produced by cilia in inner ear
development, as well as the importance of
reversing flow during heart valve formation
(2009). The accumulation of is research experience offered new prospects and he returned to France in 2009 to create his own team
in the IGBMC, where he focuses on the role
of fluid forces on embryogenesis. n
2
31
highlights
1
probing complexity
Primordial germ cells (PGC) represent a unique class of
cells. They are the embryonic precursors of the gametes,
ensuring propagation of the gene pool to the next generation and the continuation and evolution of the species.
Our main focus is to decipher the molecular mechanisms
that account for maintenance of their pluripotency. Indeed, PGC’s can be considered as totipotent cells since
following fertilization they can generate all cell types and
yield a fully functional organism.
Accordingly, most if not all, pluripotent genes are expressed by PGCs. Our goal is to identify actors involved
in the process of the PGC’s ontogeny, to study their physiological functions and to challenge them as pluripotency
reprogramming factors.
We also study the genetics of infertility in humans. Specifically, we aim to identify genes affecting human gametogenesis and therefore potentially being involved on the
PGC’s ontogeny. Based on our expertise in mouse and
human embryonic stem (ES) cells, we are setting up a new
platform dedicated to the production of pluripotent stem
cells, such as ES or induced pluripotent stem (iPS) cells.
This is done in parallel with the creation of a Biobank of
human somatic cells that serve as pathological models. <
• PGC’s ontogeny: we have identified a new gene
Tex19.1 specifically expressed by PGC and pluripotent stem cells, that is essential for the formation of male gametes. The protein presents
two well conserved domains of unknown function.
• Pluripotency: Starting from the human ES cell
model, we have recently cloned a gene coding
for a specific pluripotent stem cell protease,
which is also expressed by germ cells.
• Genetics of infertility: Studying two families,
we have cloned two genes involved in the formation of the acrosome. We are now analyzing a
third family with brothers suffering from azoospermia.
• Pathological models: We have generated the second largest (worldwide), collection of human
shaping the future
Primordial germ
cells’ (PGC) ontogeny
Being responsible for the in vitro fertilization ward of the
hospital, we believe that it is of fundamental importance
to conduct research as a continuum from basic to clinical
and from clinical to basic. In this context, we hope that our
work will highlight some of the fundamental mechanisms
in the PGC’s ontogeny, contribute to the understanding of
pluripotency and will have a clinical outcome.
Indeed, the study of genes involved in such processes will
notably clarify the biology of PGC and pluripotency but should
allow significant advances in the production of pluripotent
stem cells that can be used either as cellular models to
study the physiopathology of diseases or as a tool for cell
therapeutic, or for pharmaceutical screening.
We also aim to produce cellular models for the research
community by building a biobank of iPS cells. <
Stéphane Viville
Primordial germ cells, first
step in reproductive biology
embryonic stem cells carrying genetic disease genes. In
addition, we have implemented the reprogramming technology and produced dozens of iPS cells from normal or
pathological tissues. n
P Tropel, J Tournois, J Côme, C Varela, C Moutou, P
Fragner, M Cailleret, Y Laâbi, M Peschanski, S Viville
High efficiency derivation of human embryonic stem
cell lines following pre-implantation genetic diagnosis.
In Vitro Cellular & Developmental Biology– Animal
2010 46(3-4):376-85. Epub Mar 9. (2010).
Madanl B, Madanl V, Weber O, Tropel P, Bluml C, Kieffer E, Viville S, Fehling HJ. The strictly pluripotencyassociated gene Dppa4 is dispensable for embryonic
stem cell identity and germ cell development, but
essential for embryogenesis.
Mol. Cell. Biol. 29(11):3186-203. (2009).
1- Immunofluorescence detection
of Oct4 (red) or Tex19.1 (green) and
merge image. Top at 8 cells stage,
bottom at blastocyst stage.
2- In situ hybridization detecting
Tex19.1 mRNA on male (top) or
female embryonic gonads (bottom).
Kuntz S, Kieffer E, Bianchetti L, Lamoureux N, Fuhrmann G, Viville S. Tex19, a mammalian specific protein, with a restricted expression in pluripotent stem
cells and germ line. Stem Cells 26: 734-744. (2008).
Dam AHDM, Koscinski I, Kremer JAM, Moutou C,
Jaeger A-S, Oudakker AR, Tournaye H, Charlet N,
Lagier-Tourenne C, van Bokhoven H, Viville S. Homozygous mutation in SPATA16 is associated with male
infertility in human globozoospermia.
Am. J. Hum. Genet. 81:813-820. (2007).
After Stéphane Viville received a degree in
Pharmacy, he completed his PhD in immune
tolerence with Diane Mathis and Christophe
Benoist’s team in Strasbourg. In 1993, he
demonstrated the fundamental role of the
invariant chain. Stéphane undertook his
post-doc research with Azim Surani’s team
in Cambridge, (UK) and working on genomic
imprinting, proved the role of PEG1 in maternal behavior. In 1995, he created the Preimplantation Genetic Diagnosis Center at the
Strasbourg Hospital and also taught classes
at the Faculty of Medicine while working on
retinoic acid with Manuel Mark’s group.
In 2003, he formed his own team at the
IGBMC, focusing on primordial germ cell
ontogeny. In 2008, his team identified a new
gene involved in pluripotency (Tex19) and a
human mutation that influences acrosome
development (SPATA16). Since 2004, he has
led the Reproductive Biology Ward at the
Strasbourg Hospital. n
2
33
Regulation of gene expression, signalling and cancer
" The idea is to study in the widest sense the transcription control, in normal, physiological but also pathological states ". I. Davidson
The fundamental mechanisms regulating gene expression have been one of the major research areas
of the IGBMC, and its forerunner the LGME, for
more than 30 years. Since the initial purification
and characterization of RNA polymerase II by Pierre
Chambon and colleagues, a consistent theme has
been the identification of the machinery required for
basal and regulated transcription. The isolation of
two major transcription factors TFIIH and TFIID
proved a major advance in understanding the close
link between transcription, DNA repair and human
disease and highlighted the importance of the preinitiation complex in developmental and cell-specific
gene regulation. Currently, the Programme has incorporated the study of epigenetics and chromatin
dynamics, RNA metabolism as well as high throughput genomic and proteomics technologies as it pursues its quest to understand the regulation of gene
expression.
The study of nuclear receptors, transcription factors
whose activity is regulated by a diverse set of hor-
Functional
Genomics &
Cancer
• Fundamental mechanisms of transcription, RNA metabolism and DNA
repair : identification and characterisation of complexes involved in transcription, RNA degradation and DNA repair, role of nuclear and cellular organisation in the control of these processes.
• Epigenetic modifications, histone variants and chromatin dynamics during differentation : purification and characterization of complexes involved
in the enzymatic modification of histones and deposition of histone variants in chromatin, role of these factors in control of gene expression in
differentiation and development.
• Physiopathology and molecular biology of nuclear receptors : development of mouse models for study of nuclear receptors and their cofactors
in metabolism and disease, identification and characterisation of nuclear
receptor cofactor complexes, high throughput genomic approaches to
identify target genes and pathways.
• Signalling pathways, gene expression and cancer : integrative approaches to link basal factors, DNA repair, nuclear receptors and other
transcription regulatory factors and signalling pathways to deregulated
gene expression involved in malignant transformation, development of novel paradigms for cancer therapy through targeting epigenetic enzymes,
understanding the basis of tumor-cell selective apoptosis.
Human cancers : molecular characterisation of factors overexpressed in
breast and other human cancers, discovery, and testing of novel prognostic markers and therapeutics.
mones and metabolites and of their cofactors is the
second major theme of the Programme. The function of several receptors, principally estrogen, glucocorticoid, vitamin D3 and retinoic acid receptors
in development, physiology and disease are studied
by germ line and spatio-temporal somatic mutation
in an extensive set of recombinant mouse models.
In recent years, this approach has revealed the importance of retinoic acid signaling in the development of hepatocellular
carcinoma, and vitamin
13 Groups
D signaling in atopic
32 Staff Scientists
dermatitis and asthma.
Complementary to the
42 Postdoctoral fellows
in vivo studies are the
53 PhD students
biochemical
charac
terization of receptor
34 Engineers/Technicians
cofactors and the mole1 Assistant
cular basis of cross-talk
with other signalling
pathways.
A recurrent and transversal theme throughout the
Programme is how the normal gene regulatory mechanisms are deregulated during malignant transformation. The Programme has underlined the contribution of basal factors, transactivators, epigenetics
and nuclear receptors in the etiology and treatment
of various cancers. Bringing together the teams
working on functional genomics and on cancer in
one Programme aims to strengthen the interaction
around this common theme. The recruitment of
new groups in epigenetics, nuclear organization and
DNA repair underscores the commitment of the
Programme to pursue the study of the links between
fundamental nuclear processes and cancer. n
35
highlights
• Cancer: Using genetic approaches, we have developed a mutant mouse line (IkL/L) in which
Ikaros expression is knocked down to 10% of
normal levels. We have shown that Ikaros exerts
its tumor suppressor activity by repressing the
transcription of target genes associated with the
Notch pathway in developing T cells. Notch activation is therefore an early and critical event
during T-cell leukemogenesis in IkL/L mice.
Moreover, we have provided evidence that the
Ikaros gene is mutated in human T-ALLs.
1
probing complexity
Hematopoiesis is characterized by the development of
hematopoietic stem cells into pluripotent progenitor
cells and finally into mature blood cells. This orderly and
continuous process involves self-renewal, cell fate choice,
differentiation and proliferation. Transcription factors are
responsible for coordinating these processes but their
expression must be tightly regulated to prevent hematological malignancies. In this context, we are interested in the
following questions.
How do transcription factors control hematopoiesis ?
How do alterations in their function contribute to leukemogenesis ?
In the past, we have shown that retinoic acid receptor
alpha and PU.1 play important roles in granulocyte and
erythroid differentiation, respectively. Our current studies
focus on the Ikaros family of transcription factors, which
act mainly as transcriptional repressors through association with chromatin remodeling complexes. Ikaros (Ikzf1)
is a zinc finger protein expressed by all hematopoietic
cells. Ikaros is crucial for lymphocyte differentiation and
homeostasis and also functions as a tumor suppressor in
T and B cells. Furthermore, loss of Ikaros has been detected in human T- and B-cell acute lymphoblastic leukemias
(ALLs). The molecular mechanisms responsible for these
activities remain unclear.<
shaping the future
Hematopoiesis and
Leukemogenesis in the Mouse
Today we are dissecting the molecular pathways
regulated by the Ikaros family. We will apply this
knowledge and our tools to understand how
Ikaros family members control hematopoietic
cell differentiation, stem cell function and
chromatin remodeling.
We are using the Ikaros-deficient T-ALL model
to address fundamental issues regarding T-cell
leukemogenesis, such as the existence and
identity of leukemia initiating cells and the role
of the Notch receptors. <
Philippe Kastner
Susan Chan
Two converging careers
• Hematopoiesis: In the B-cell lineage, we have
shown that Ikaros blocks the development of
immature pro/preB cells in the bone marrow
and controls isotype selection during class switch
recombination in mature splenic B cells. In the
dendritic cell (DC) lineage, we have shown that
Ikaros is specifically required for the differentia-
Susan Chan obtained her Bachelor’s degree
at the University of California, Berkeley and
her PhD in immunology at the University of
Pennsylvania in the U.S. In 1991, she moved
to Strasbourg to studyT-cell differentiation as
tion of a subset of DCs called plasmacytoid dendritic cells.
A Marçais, R Jeannet, L Hernandez, J Soulier, F
Sigaux, S Chan and P Kastner. Genetic inactivation of
Ikaros is a rare event in human T-ALL.
Leukemia Res. 4:426-429. (2010).
• Ikaros family members: More recently, we have generated
the first knock-out mouse line for Helios (Ikzf2), another
member of the Ikaros family. We are currently investigating how Helios plays a role in hematopoiesis. n
a post-doctoral fellow with Diane Mathis and
Christophe Benoist. There, she met Philippe
Kastner, a scientist in Pierre Chambon’s
lab. A graduate of Ecole Polytechnique, he
was working at the time on retinoic acid
receptors and developing mutant mouse
models to study their function. In 1997, they
started a new team together at the IGBMC.
Q Cai, A Dierich, M Oulad-Abdelghani, S Chan and P
Kastner. Helios deficiency has minimal impact on T
cell development and function.
J Immunol. 183:2303-2311. (2009).
Now they study how transcription factors
M Sellars, B Reina-San-Martin, P Kastner and S
Chan. Ikaros controls isotype selection during class
switch recombination.
J Exp Med. 206:1073-1087. (2009).
development. n
E Kleinmann, AS Geimer Le Lay, M Sellars, P Kastner
and S Chan. Ikaros represses the transcriptional
response to Notch signaling in T-cell development.
Mol Cell Biol. 28:7465-7475. (2008).
regulate hematopoiesis and how mutations
in
2
these
proteins
promote
leukemia
1- Specific gene expression signatures define various
subtypes of murine T-cell leukemias.
2- Activation of Notch1 transcription from an intragenic
promoter in Ikaros-deficient T-cell leukemias: visualization by ChIP-seq of histone H3 acetylation over the
Notch1 gene in IkL/L tumors with an intact Notch1 gene
(black) or with a deletion of the Notch1 promoter (red).
37
highlights
• The TAF4 subunit of transcription factor
TFIID plays an important role in diverse signaling pathways as an essential co-activator for
CREB and the RARs. Genetic study of TAF4null MEFs and its inactivation in the mouse
epidermis revealed novel functions in regulating
the TGF-beta and EGF signaling pathways and
highlighted its role as a cell autonomous and cell
non-autonomous tumor suppressor.
1
probing complexity
The main focus of our work over the last several years
has been to understand the role of TFIID subunits such
as TAF4 or paralogues such as TAF4b, TRF2 or TAF7L
in gene expression. The study of TAF4 function in cells
derived from genetically modified mice in vitro and tissue-specific knockouts in vivo revealed novel facets of its
function as a regulator of multiple signaling pathways and
cell proliferation, as well as a tumor suppressor. The study
of TAF4 as a co-activator for the retinoic acid receptors
(RARs), allowed us to decipher the molecular mechanism
of cross-talk between the RA and TGF-beta signaling pathways that promotes cell proliferation. We completed this
cycle of experiments by using ChIP-chip to identify RAR
occupied loci and to target genes revealing the importance
of cell-specific binding site occupancy in determining the
biological response to RA.
More recently, we were responsible for setting up high
throughput sequencing techniques at the IGBMC. The
implementation of these technologies has profoundly altered our experimental Programme over the last few years allowing us to ask different sets of questions. We have begun
to use these techniques to understand the role of various
transcription factors in developmental and pathological
processes. <
shaping the future
Structure and function of the general
transcription factor TFIID
The development of high-throughput genomic technologies
(ChIP-seq, RNA-seq) facilitates the characterization of
complex gene regulatory networks. We are using these
approaches to address the functions of transcription factors
such as MITF, its co-factors and target gene products
in the proliferation of malignant melanoma, the TEAD
family in muscle differentiation and regeneration and the
RARs and RAR-regulated transcription factors in neuronal
differentiation of ES cells and tumor suppression.
We are also pursuing our characterization of TAF4 through
the generation of novel tissue-specific knockout mice. We
have identified a novel TAF4-containing TFIID sub-complex
that is abundant in several cell types and are investigating
its potential function by comparing the genomic occupancy
of TAF4 and TBP in these cells. <
Irwin Davidson
Regulation of transcription
in differentiation and cancer
• We characterized the molecular basis of the
cross-talk between the RA and TGF-beta signaling pathways in MEFs. RA induces TGF-beta
dependent autocrine growth by directly activating the expression of the TGF-beta3 ligand and
the secreted mitogen connective tissue growth
factor (CTGF). Transient RA treatment is sufficient to set up a positive feedback loop between
these two mitogens.
Delacroix L, Moutier E, Altobelli G, Legras S, Poch
O, Choukrallah M-A, Bertin I, Jost B, and Davidson
I. Cell-specific interaction of retinoic acid receptors
with target genes in mouse embryonic fibroblasts
and embryonic stem cells.
Mol. Cell Biol. 30: 231-244. (2010).
After obtaining his PhD at the University of Glasgow
on the herpes virus (1985), Irwin Davidson became
a post-doc fellow with Pierre Chambon’s group in
Strasbourg, working on the identification of transcription factors interacting with the SV40 enhancer.
• We used ChIP-chip and transcriptomics/RNA-seq to
identify RAR binding sites and target genes in MEFs and
ES cells. More than 750 RAR-occupied promoters were
identified, in which the vast majority were cell specifically
occupied. Our results reveal that differences in the chromatin landscape regulate accessibility of RARs to their
target loci modulating the repertoire of target genes that
can be regulated and the biological effects of RA. n
In 1990, he became interested in the mechanisms
responsible for transcription activation and in 1993
he participated in the identification of the TFIID factor and its role as a co-activator. Irwin then focused
on cloning genes and encoding different TFIID subunits through biochemical, structural and genetic
approaches. He also discovered the important role
of the histone fold motif in TFIID organization. At
the beginning of 2000, he began to study the role of
Fadloun, A., Kobi, D., Delacroix, L., Dembélé, D.,
Michel, I., Lardenois, A., Tisserand, J., Losson, R.,
Mengus, G., and Davidson, I. Retinoic acid induces
TGFb-dependent autocrine fibroblast growth. Oncogene. 27(4):477-89. (2008).
TBP and its paralogueTRF2 in the mouse, where he
1- Mislocalisation of H1T2
in TRF2-null mouse haploid
spermatids.
2- Senescent human 501 melanoma cells.
Fadloun, A., Kobi, D., Pointud, J-C., Kumar, I., Teletin,
M., Bole-Feysot, C., Testoni, B., Mantovani, R.,
Metzger, D., Mengus, G., and Davidson, I. The TFIID
subunit TAF4 regulates keratinocyte proliferation
and has cell-autonomous and non-cell-autonomous
tumour suppressor activity in mouse epidermis.
Development. 134(16):2947-58. (2007).
demonstrated the specific role of TRF2, in transcription regulation in male germ cells.
This work also led to the discovery of novel histone
variants and chromatin-associated proteins that
specify nuclear domains within the developing spermatozoa. Irwin’s group characterized the structure
and functions of theTFIID subunitTAF4 and revealed
its role in various signaling pathways. n
2
39
highlights
1
probing complexity
Transcription, one of the key steps of gene expression in
response to different stimuli of the organism like stress or
hormones, requires a combination of factors. The deleterious
action of physical or chemical agents that create lesions in the
DNA disrupts the expression of genes. If these lesions are not
removed by efficient repair systems they will be at the origin
of mutations that can lead to cancer and aging. TFIIH, a
multi-subunit complex that we are studying plays a pivotal
role in both the transcription of genes and their repair.
Mutations in some of the subunits of TFIIH are responsible
for three genetic diseases (xeroderma pigmentosum (XP), trichotyodystrophy (TTD) and Cockayne syndrome (CS)),
the phenotypes of which result from defects in both DNA
repair and gene expression. For instance, TTD patients present brittle hairs and nails, that cannot account from a defect
in DNA repair and that can be recapitulated in mouse TTD
models. With the help of biochemical, genetic and cellular
biology we study these diseases and consequences of deregulation of gene expression and repair in various cellular systems and animal models.<
• Over the last five years we have dissected the
role of each of the TFIIH subunits and explained
the molecular defects in transcription and repair
responsible for the phenotypes of XP and TTD
patients mutated in TFIIH subunits. We have
recently identified the tenth subunit of TFIIH
and demonstrated its specific involvement in
DNA repair; mutation in this subunit results
in TTD group A disorder. We showed that the
CAK module was not part of TFIIH when removing DNA lesions but was specifically devoted to the transcription function of TFIIH.
• In transcription, we showed that CAK was
not only involved in the phosphorylation of the
RNA polymerase II but also in the phosphorylation of several nuclear receptors e.g. retinoic
acid, peroxisome proliferator-activated and thyroid hormone receptors. The phosphorylation
Ueda, T., Compe, E., Catez, P., Kraemer, K.H.,
and Egly, J.M. Both XPD alleles contribute to the
phenotype of compound heterozygote xeroderma
pigmentosum patients.
J Exp Med. 206:3031-3046. (2009).
shaping the future
Genome expression
and repair
We aim to:
● better understand the mechanisms of gene expression and DNA repair and to elucidate the dynamic interactions between these two pathways.
● explain the biochemical phenotypes of transcription/
repair syndromes, focusing on the hormonal dys-regulation that leads to these various phenotypes. In addition, it will allow us to gain extensive insights into the
physiology of nuclear hormones.
● employ sophisticated technologies to obtain mechanistic details on DNA repair. These include :
- Screening of genomic siRNA libraries to identify
new DNA repair factors
- Follow up TTD/XPD diseases in vivo in animal models using a robotic biopsy collection and Computed
Tomography (CT) coupled with 3-D tissue reconstruction in collaboration with IRCAD (Strasbourg).
● further our understanding of molecular effects induced by anti-cancer agents, in collaboration with a
pharmaceutical company.<
of these nuclear receptors by TFIIH is required for their
recruitment and stabilization to their DNA cognate sequence, leading to the ligand-dependent transactivation
of their responsive genes. Mutation in XPD subunit of
TFIIH (as found in XP-D patients) destabilize the interaction between the CAK complex and the core TFIIH,
leading to nuclear receptor phosphorylation defect and
impaired transactivation of specific genes. n
Coin, F., Oksenych, V., Mocquet, V., Groh, S., Blattner,
C., and Egly, J.M. Nucleotide excision repair driven
by the dissociation of CAK from TFIIH.
Mol Cell. 31:9-20. (2008).
1- Coomassie blue staining of the highly purified
nucleotide excision repair
(NER) factors required to
remove DNA damages.
2- Transactivation mechanism mediated by the
phosphorylation of nuclear
receptors by TFIIH.
Compe, E., Malerba, M., Soler, L., Marescaux, J.,
Borrelli, E., and Egly, J.M. Neurological defects in
trichothiodystrophy reveal a coactivator function of
TFIIH. Nat Neurosci. 10:1414-1422. (2007).
Coin, F., De Santis, L.P., Nardo, T., Zlobinskaya, O.,
Stefanini, M., and Egly, J.M. p8/TTD-A as a RepairSpecific TFIIH Subunit. Mol Cell. 21:215-226. (2006)
Frédéric Coin
Jean-Marc Egly
Transcribing and
repairing DNA.
Educated in biochemistry, Jean-Marc Egly
became interested in two main cellular
mechanisms, DNA transcription and repair.
Besides their fundamental character, his works
contributed to many breakthroughs for the
comprehension of cancerogenesis and rare
genetic disorder mechanisms. In 1985, he
started his team in Strasbourg. In 2006, he
was appointed president of the ARC scientific
council and, in 2007, special advisor for the
general director of Inserm.
Frédéric Coin was a PhD student in JeanMarc Egly’s team and revealed in 1998 that
mutations on helicases XPD and XPB observed
in Xeroderma pigmentosum affected the
transcriptional function of TFIIH. In 2004
Frédéric isolated the 10th subunit of TFIIH
involved in trichothiodystrophy (TTD). Their
work then continued on the link between
genome expression and repair. The team also
showed TFIIH factor implication in Rift valley
viral infection in collaboration with the Pasteur
Institute. n
2
41
highlights
• Nuclear receptor ligand action: Identification
of the structural and mechanistic basis of ligand
action, including agonists, inverse agonists, and
neutral, partial and full antagonists
• Description of the mechanistic basis and
cancer therapeutic potential of two apoptogenic rexinoid-based therapeutic paradigms. This
work allows for the preparation of clinical studies.
1
probing complexity
Our interest is to understand the mechanisms of signal
transduction and epigenetic (de)regulation in normal cells
and cancer, which are relevant for the development of novel
therapeutic paradigms. Based on our expertise on nuclear
receptors we first develop global systems biology approaches
to deconvolve receptor signaling complexity and aberrant
(epigenetic), signaling upon tumorigenic transformation
and study the mechanisms and therapeutic potential of cancer-selective apoptosis pathways induced by various signaling drugs and epigenetic modulators. Our studies involve
a plethora of genome-wide technologies and the corresponding development of bioinformatics tools.
One emphasis of our work is to decipher the mechanisms
underlying the cancer-selectivity of apoptogenic TRAIL
signaling. We use the obtained knowledge to devise novel
therapeutic tools and study the contribution of this pathway
to the action of (epi-) drugs. Studies on the role of the senescence-mediated secretome on TRAIL action and the epigenetic alterations during cellular senescence address the link
between cancer and aging.
Our work benefits from the integration and coordination of
several national and European consortia, which provide the
necessary multidisciplinary input and a close link to the local
hospital (HUS). <
shaping the future
From nuclear receptor action
to novel paradigms for cancer therapy action
We will expand our bioinformatics competence to facilitate
large-scale data analyses from genome-wide studies, which
is an inevitable component of future biomedical research.
By such global analyses we will identify sub-routines and
key networks in a given programme, such as estrogens or
retinoic acid signaling, integrating the (epigenetic) action of,
and crosstalk between co-regulators.
We will decrypt the molecular and structural features
underlying the tumor-selectivity of the TRAIL pathway. There
is no doubt that an understanding of this evolutionarily
developed tumor defence system will lead to an entirely
novel class of cancer therapeutics, devoid of the (geno)
toxicity of current chemo/radiotherapy.
We will continue using our expertise to generate novel (epi-)
drugs for improved cancer therapies.<
Towards novel anticancer
therapies
• Identification of the convergence of several
divergent cancer therapeutics, including
retinoids and HDAC inhibitors, on the TRAIL
pathway.
• Discovery of the first triple-action epi-drug (patented)
for cancer therapy and demonstration of strong anticancer
activity and drug action in tumor cells of animal models
treated in vivo.
Pavet, V., Beyrath, J., Pardin, C., Morizot, A., Lechner,
M.C., Briand, J.P., Wendland, M, Maison. W., Fournel,
S., Micheau, O., Guichard, G. and Gronemeyer, H.
(2010). Multivalent DR5-selective peptides activate
the TRAIL death pathway and exert tumoricidal activity in vivo. Cancer Res. 70:1101-10. (2010).
Hinrich Gronemeyer
• Discovery of the crosstalk between histone
acetyltransferases and methyltransferase CARM1, which
specifies estrogen sub-programmes and is altered during
breast cancer progression. n
Germain, P., Gaudon, C., Pogenberg, V., Sanglier, S.,
Van Dorsselaer, A., Royer, C.A., Lazar, MA., Bourguet,
W. & Gronemeyer, H. (2009). Differential action on
coregulator interaction defines inverse retinoid agonists and neutral antagonists.
Chemistry & Biology. 16:479-89. (2009).
1-MS275 induces apoptosis in the
blasts of individuals with acute myeloid
leukemia.
2- Epigenetic information provided
by chromatin modifications and
non-coding RNAs contributes to
transcriptional regulation and genomic
architecture.
Shankaranarayanan, P., Rossin, A., Khanwalkar, H.,
Jacobson, A., de Lera, A. R., Altucci, L., and Gronemeyer, H. (2009). Growth factor-antagonized rexinoid
apoptosis involves permissive PPAR /RXR heterodimers to activate the intrinsic death pathway by NO.
Cancer Cell. 16:220-31 (2009).
Chemist by training, Hinrich Gronemeyer
developed a strong interest in nuclear receptor (NR) signaling during his PhD studies
on the chromatin-regulatory functions of the
steroid hormone ecdysone, using a photochemical approach. In 1980, he joined Pierre
Chambon’s team in Strasbourg as a post-doc
fellow, where he purified and contributed to
cloning of the progesterone and glucocorticoid receptors.
After two years at the Ludwig Institute for
Cancer Research, Hinrich returned to Strasbourg to start his own group. In 1989 he
predicted the existence of NR co-regulators
and in 1996 he cloned TIF2 and established
the first 3D structures of a ligand-binding domain with Dino Moras. Thereafter, Hinrich’s
work has focused increasingly on therapeutic applications, discovering in 2001 the
TRAIL connection. In collaboration with chemists and the pharmaceutical industry, his
team developed several novel therapeutic
paradigms. Since 2005, Hinrich is the coordinator of the Epigenetic Treatment of Neoplastic Disease (EPITRON) consortium. n
2
43
highlights
• Chromatin remodeling:
We discovered the molecular mechanism of
chromatin remodeling by drosophila NURF.
NURF remodels chromatin by sliding nucleosomes along DNA.
• Gene regulation:
We have shown that the histone variant
macroH2A directly binds PARP-1 and inactivates transcription by down-regulating PARP-1
enzymatic activity.
1
probing complexity
The main research activity of our group is to study the role
of histone variants and their deposition machineries in the
epigenetic control of human genome activity at the genomewide level.
Among the various epigenetic memory mechanisms, the local replacement of canonical histones within the nucleosome
by variant histones has the potential to affect considerably
the activity of the corresponding genomic regions. Indeed,
nucleosomes bearing histone variants have distinct structures
and functional activities in vitro and some histone variants
are incorporated at specific genomic locations. Our laboratory is focusing on the role of histone variants in gene regulation and genome integrity. We have recently implicated
macroH2A in PARP-1 enzymatic activity and transcription
regulation (Ouararhni et al., 2006), and discovered a new
link between histone variants, transcription factors and noncoding RNA (unpublished results). This association with
transcription factors and non-coding RNA is novel and will
certainly help us to understand how chromatin domains are
established and how epigenetic information is stored and
transmitted to daughter cells. Alteration of these epigenetic
marks is associated with developmental disorders and cancer.
shaping the future
Chromatin and
epigenetic regulation
Our major goal is to study the epigenetic mechanisms
underlying gene regulation using mammalian cells as a
model system. More specifically, we are interested in
addressing how histone variants are deposited at specific
chromatin loci and how this impacts chromatin structure
and gene regulation.
We are also interested in the role of non-coding RNA in
histone deposition. The involvement of non-coding RNAs
in targeting molecules adds another level of complexity
to chromatin regulation. Interestingly, histone variants
deposition complexes contain several non-coding RNAs.
However, the mechanism by which these RNAs function is
unknown. One of our future aims will be to elucidate how
these interactions influence histone deposition and gene
regulation.<
Ali Hamiche
A chromatin biochemist
• Histone deposition:
We have identified and characterized the first
vertebrate histone chaperone, involved in the
deposition of CenpA at centromeres.
We have investigated in detail the molecular
mechanism of the histone variant H3.3 deposition and found that the death-associated pro-
Drané P, Ouararhni K, Depaux A, Shuaib M and
Hamiche A. The death-associated protein DAXX is a
novel histone chaperone involved in the replicationindependent deposition of H3.3.
Genes Dev. 24(12):1253-65. (2010).
tein DAXX and the chromatin-remodeling factor ATRX
are crucial components of the H3.3 deposition machinery.
Our data argues that DAXX functions as a histone chaperone, involved in the replication-independent deposition
of H3.3, thus linking apoptosis to gene regulation. Our
findings also provide a clue as to how mutations in the
ATRX gene lead to the human genetic diseases of a-thalassemia and X-linked mental retardation. n n
Shuaib M, Ouararhni K, Dimitrov S and Hamiche A,
(2010). HJURP Binds CENP-A via a highly conserved N-terminal domain and mediates its deposition at centromeres. Proc. Natl. Acad. Sci. USA.
107(4):1349-54. (2010).
1- Specific marking of chromatin
by histone variants.
2- Schematic representation of
the assembly of the core histones
into the nucleosome.
Ouararhni K, Hadj-Slimane R, Ait-Si-Ali S, Robin P,
Mietton F, Harel-Bellan A, Dimitrov S, Hamiche A. The
histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity.
Genes Dev. 20(23):3324-36. (2006).
Ali Hamiche graduated from the Pierre and
Marie Curie University (Paris VI), where
he
also obtained a PhD on chromatin
structure and function. Recruited in 1996 as
a Research Scientist with Hélène RichardFoy’s team (LBME, Toulouse), he worked
on conformational transitions of the
nucleosome during transcription.
In 1998 he received a Human Frontier postdoctoral fellowship and joined Carl Wu’s
laboratory at the National Cancer Institute,
(NIH) in Bethesda, MD, US.
In 1999 he discovered the mechanism of
chromatin remodeling by the Drosophila
NURF complex . In 2003, he joined the André
Lwoff Institute (Villejuif) as a young group
leader to work on histone variants, and two
years later he joined the IGBMC to create
a new team that currently focuses on the
same topic. n
<
2
45
highlights
1
probing complexity
The last decade has seen an enormous rise in the interest
for nuclear receptors (NRs), because of their central role
in the coordination of development and homeostasis,
through their ability to transduce hormonal signals into
modulation of gene activity. Our main goal is to study, under physiological and pathophysiological conditions in the
whole organism, the function and interdependence of signaling pathways that are regulated by various nuclear receptors [e.g. the retinoid X receptors (RXRs), the retinoic
acid receptors (RARs), the peroxisome proliferator-activated receptors (PPARs), the vitamin D3 receptor (VDR),
the oestrogen receptors (ERs), the androgen receptor (AR)
and the glucocorticoid receptor (GR)] in different organs
(e.g. skin, lung, intestine, skeletal muscle and reproductive organs). In that respect, we have used our site-directed
cell-specific temporally-controlled somatic mutagenesis
method, which allows the generation of somatic mutations
in the mouse of any given gene, at any chosen time and
in any specific cell type. Interestingly, as this genetic tool
is also of great value to generate mouse models of human
cancers, the knowledge gained from their analyses should
contribute to the development of new cancer therapies. <
• Through phenotypic analyses of various mouse
mutants, we have revealed that RXR/RAR and
RXR/VDR heterodimers, as well as GR, control
the expression of the cytokine “thymic stromal
lymphopoietin (TSLP)” in epidermal keratinocytes, and demonstrated that this cytokine plays
a key role in initiating the development of a skin
and systemic disease mimicking human atopic
dermatitis.
• Our studies also revealed that enhanced TSLP
expression in mouse epidermal keratinocytes aggravates experimental allergic asthma, indicating
that keratinocyte-produced TSLP may represent
an important factor in the “atopic march” that
links atopic dermatitis and asthma.
• By analyzing mutant mice in which PPARβ is
selectively ablated in skeletal muscles, we have
demonstrated that this nuclear receptor is instru-
Z. Zhang, P. Hener, N. Frossard, S. Kato, D. Metzger,
M. Li and P. Chambon Thymic stromal lymphopoietin
overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc. Natl. Acad. Sci.
U.S.A. 106:1536-1541. (2009).
shaping the future
Genetic dissection of nuclear receptor
signaling in the mouse
Our projects are aimed at further characterizing the
physiological role of nuclear receptors, the mechanism
of their action at the molecular, cellular and organismal
levels, and their implication in the pathogenesis of
human diseases. We will analyze in skeletal muscles the
functional role of AR, GR and PPARs, and of some of
their co-regulators (SRC-1, TIF2 and SRC-3; NCoR and
SMRT), in order to characterize the signaling pathways
controlled by these factors and to identify new drug
targets to prevent or treat metabolic and muscle
diseases. The role played by TSLP and nuclear receptors
in the pathogenesis of atopic dermatitis and asthma
will be further investigated, as well as their function in
intestinal epithelial cells, where they could be involved
in the control of the immune response to commensal
bacteria. This latter study and related studies should
reveal some of the molecular mechanisms through
which the dialog between the microbiota and intestinal
epithelial cells contributes to homeostasis and disease
of the intestine. <
Pierre Chambon
Daniel Metzger
All about nuclear receptors
mental in myocytes to the maintenance of oxidative fibers,
and have shown that fiber type switching is likely to be the
cause, and not the consequence of metabolic diseases such
as obesity and diabetes.
• By ablating the tumor suppressor gene PTEN selectively
in epithelial cells of the mouse prostate, we have generated
a model mimicking human invasive prostatic adenocarcinoma. n
C. K. Ratnacaram, M. Télétin, M. Jiang, X. Meng,
P. Chambon and D. Metzger. Temporally-controlled
ablation of PTEN in adult mouse prostate epithelium
generates a model of invasive prostatic adenocarcinoma. Proc. Natl. Acad. Sci. U. S. A. 105:2521-2526.
(2008).
1- Immunohistochemical detection
of RyR1 (Green) and DHPRβ (red) in
mouse tibialis muscle. Nuclei are stained
with DAPI (blue).
2- Immunohistochemical detection
of TSLP in mouse epidermal keratinocytes.
M. Schuler, F. Ali, C. Chambon, D. Duteil, J-M. Bornert, A. Tardivel, B. Desvergne, W. Wahli, P. Chambon
and D. Metzger PGC1α expression is controlled in
skeletal muscles by PPARβ, whose ablation results
in fiber type switching, obesity and type 2 diabetes.
Cell Metabolism 4:407-414. (2006).
Pierre Chambon was ranked fourth among
most prominent life scientists for the 19832002 period. Honorary Professor at the Collège
de France and Emeritus Professor at the Faculté de Médecine, he was the founder and first
Director of the IGBMC and the Institut Clinique
de la Souris (ICS).
During his PhD training performed under
Pierre Chambon’s supervision, Daniel Metzger
revealed a striking conservation of the molecular mechanisms underlying transcriptional activation across eukaryotes. He was recruited in
1995 at the CNRS, and established CreERT2, an
efficient system to perform spatio-temporally
controlled targeted somatic mutagenesis in
the mouse, which is now used worldwide. Daniel then applied this mouse mutagenesis system to investigate the role of nuclear receptors
in vivo. These studies brought major insight on
the functions of nuclear receptors, notably in
intermediary metabolism and skeletal muscle.
He is presently co-leading with Pierre Chambon a research group on functions of nuclear
receptors in homeostasis and diseases. n
2
47
highlights
• The DNA damage sensors Parp1 and Parp2
contribute to the resolution of AID‐induced
DNA breaks during CSR by facilitating DNA
repair by the alternative‐NHEJ pathway and by
suppressing oncogenic translocations.
• The transcription factor Ikaros plays a key role
in establishing a transcriptional competition
between switch regions in individual cells that
is critical for isotype specification during CSR.
1
probing complexity
The functional properties of antibodies are shaped during
immune responses through somatic hypermutation (SHM)
and class switch recombination (CSR). SHM modifies
antibody affinity, while CSR modulates antibody effector
functions by replacing the antibody isotype expressed. These
reactions are unusual among somatic cells in that they are
initiated by DNA damage and both have been implicated
in the development of cancer. They are triggered by Activation Induced Cytidine Deaminase (AID), an enzyme that
deaminates cytidine residues in DNA. B lymphocytes are
particularly prone to malignant transformation and it has
been proposed that DNA damage incurred during CSR or
SHM may account for this cancer susceptibility. Such damage might be due to bystander gene targeting by AID or
alternatively to aberrant DNA repair. AID has the potential
to inflict significant collateral DNA damage. Nevertheless,
most B cells expressing AID do not suffer widespread mutation or chromosome instability and only a few non‐immunoglobulin genes are known to be mutated. Therefore,
it appears that specific regulatory mechanisms restrict this
potential to the appropriate cell type and loci. Despite great
progress, how specific AID targeting is achieved in vivo and
how AID‐induced DNA damage is accurately repaired is not
known.<
shaping the future
Molecular biology
of B cells
SHM and CSR are initiated by programmed DNA damage
induced by AID. This type of damage is normally restricted
to antibody genes. However, aberrant targeting of AID to
nonimmunoglobulin genes and/or abnormal repair of AID
induced lesions may account for the increased propensity
for malignant transformation in B cells.
Our projects will provide insight into the molecular
mechanisms that control AID activity and that enforce the
accurate repair of AID‐induced DNA damage. Furthermore
they will allow us to further understand the complex
problem of double stranded DNA break detection, signaling
and repair. The conclusions drawn from these projects
will not only foster our future studies on B cell repertoire
diversification, but will also have important implications for
the fields of DNA repair and cancer. <
Bernardo Reina
B cell diversification and
humoral immunity
• AID associates with KAP1 and HP1 in a complex that is tethered in vivo to transcribed switch
regions bearing the H3K9me3 mark. These
results provide a novel and original AID targeting mechanism that accounts for the epigenetic
modifications induced at the immunoglobulin
heavy chain locus during CSR.
• We have developed an innovative tool that allows us to
homogeneously induce double stranded DNA breaks at a
single genomic locus of known sequence, and for the first
time, to isolate and identify novel factors recruited into
DNA repair foci. n
Robert, I., Dantzer, F. and Reina‐San‐Martin, B. Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c‐
myc translocations during immunoglobulin class switch
recombination. J Exp Med. 206:1047‐56. (2009).
Sellars, M., Reina‐San‐Martin, B., Kastner, P. and Chan, S.
Ikaros controls isotype selection
during immunoglobulin class switch recombination.
J Exp Med. 206:1073‐87. (2009).
1- Histological section of a lymph
node showing germinal centers, the
sites of B cell receptor diversification
by SHM and CSR.
2- Collateral damage to the genome
triggered by AID expression.
Robbiani, D.F., Bothmer, A., Callen, E., Reina‐San‐Martin,
B., Dorsed, Y., Difilippantonio, S., Bolland, D.J., Chen, H.T.,
Corcoran, A.E., Nussenzweig, A. and Nussenzweig, M.C.
AID is required for the chromosomal breaks in c‐myc that
lead to c‐myc/IgH translocations.
Cell. 135:1028‐38. (2008).
Reina‐San‐Martin, B., Chen, J., Nussenzweig, A. and
Nussenzweig, M.C. Enhanced intraswitch region recombination during immunoglobulin class switch recombination
in 53BP1‐/‐ B cells. Eur J Immunol. 37:235‐9. (2007).
Bernardo Reina obtained a PhD in Immunology at the Pasteur Institute (Paris). There
he revealed that Trypanosoma cruzi (etiological agent of Chagas’ Disease) produces a
B cell mitogen that enhances the susceptibility of the host and proposed a novel and
alternative vaccination strategy that can be
generalized to other pathogens of medical
importance (2000). Bernardo then relocated to New York, USA for a postdoctoral stay
with Michel Nussenzweig at the Rockfeller
University and the Howard Hughes Medical Institute (HHMI) and began working on
somatic hypermutation (SHM) and class
switch recombination (CSR), two mechanisms initiated by Activation Induced cytidine Deaminase (AID), which are essential
for establishing highly specific and adapted
humoral responses. He implicated the DNA
damage response pathway in the mechanism of CSR (2001) and proposed that its
role is to induce chromatin conformational
changes that facilitate long-range recombination (2003-2005). In 2006, he created his
own group at the IGBMC. n
2
49
highlights
• Cancer and metabolism: We have identified
MMP11 as an unusual matrix metalloproteinase
that favors cancer cell invasion through the reprogramming of cancer-associated adipocytes (CAAs)
towards fibroblast-like cells.
1
probing complexity
The natural history of breast cancer involves progression
through clinical stages starting with abnormal epithelial proliferation, progressing into in situ and invasive carcinomas,
concluding in metastatic disease. The progression from in situ
to invasive carcinoma is a critical step in terms of prognosis and
relies on cancer and normal cells present in the tumor. In this
context, MMP11 identification as a secreted mesenchymal factor associated with invasive breast cancer was a pioneer finding
in the field of invasion. Using a variety of cellular and mouse
models of tumorigenesis, MMP11 expression by stromal cells
was shown to be crucial in the invasive process. Moreover, prognostic studies indicated its association with a poor patient outcome. Indeed, the Oncotype DX (Genomic Health, Redwood
City, CA) that predict breast cancer relapse includes MMP11
dosage.
Breast cancer is a heterogeneous disease that is currently classified into 3 main classes: luminal (estrogen receptor (ER) and
progesterone receptor (PR) positive), HER2 (a member of
the epidermal growth factor (EGF) receptor family) positive
and basal-like, which is primarily PR, ER and HER2 negative (ie, triple negative). By comparing benign and malignant
breast biopsies, we have identified several genes including pS2/
TFF1 expressed in luminal tumors and TRAF4, MLN51 and
STARD3 which are specifically expressed in HER2 tumors. All
of these genes are expressed by cancer cells and our research is
focused on the function of the respective proteins. <
• Cancer and mRNA metabolism: We have characterized the RNA binding protein MLN51 as a
member of the exon junction complex (EJC) that
controls gene expression at the mRNA level, and
showed that MLN51 is essential for the survival of
cells under stress.
shaping the future
Molecular and cellular biology
of breast cancer
We study breast cancer via the functional characterisation of selected genes and pathways. Obesity is a
poor prognosis factor. We have shown a connection
between MMP11, cancer progression and adipose
tissue. We are investigating the molecular mechanisms behind MMP11 action on cancer-associatedadipocytes (CAAs). TFF1, alias pS2, is a secreted factor. Despite being a classic ER-induced gene, its role
in breast cancers remains unclear. We are exploring
the molecular basis of TFF1 function. HER2-positive
breast cancer, usually classified as high risk, is hardly a homogeneous disease. Indeed, some patients
do not experience relapse, and HER2-targeted therapies show variable response. TRAF4, MLN51 and
STARD3 are overexpressed in HER2-positive tumors.
Their molecular functions in normal and malignant
conditions are under examination. They may help to
define HER2-positive tumor subsets. Altogether, our
studies will reveal targets and molecular pathways
that will help to understand the natural history of
breast cancer and will be translated into the clinic. <
Marie-Christine Rio
Development & progression
of breast cancer
• Cell polarity: We have demonstrated that the
TRAF4 adaptor protein is essential during development and acts in epithelial cells as a tight junctionassociated dynamic signaling component.
• Translational research: Recently, in collaboration with
the Breast Clinical Center in Strasbourg, we showed that
hormone-dependency is underestimated in pregnancy-associated breast cancers and should be considered for patient
management. n
Tumor necrosis factor receptor-associated factor 4
is a dynamic tight junction-related shuttle protein involved in epithelium homeostasis. Kédinger V, Alpy F,
Baguet A, Polette M, Stoll I, Chenard MP, Tomasetto
C, Rio MC. PLoS One. 3(10):e3518; (2008).
1- Transverse section of a human mammary gland normal
lobule showing honeycomb
tight junction structure with
TRAF4 (green) co-localizing
with occludin (red)
.2- X-ray computed tomography (microCT) of metastasis
development (green) in the
lungs of live mouse.
Matrix metalloproteinase-11/stromelysin-3 exhibits
collagenolytic function against collagen VI under
normal and malignant conditions. Motrescu ER,
Blaise S, Etique N, Messaddeq N, Chenard MP, Stoll
I, Tomasetto C, Rio MC.
Oncogene. 27(49):6347-55. (2008).
The exon-junction-complex-component metastatic
lymph node 51 functions in stress-granule assembly.
Baguet A, Degot S, Cougot N, Bertrand E, Chenard
MP, Wendling C, Kessler P, Le Hir H, Rio MC, Tomasetto C. J Cell Sci. 120(Pt 16):2774-84. (2007).
Catherine Tomasetto
Catherine Tomasetto met Marie-Christine Rio
in 1989 while she was a PhD student in Pierre
Chambon’s laboratory. Marie-Christine had
conducted clinical research for developing
tests for hormonal receptor dosage in prostate
cancer at the Strasbourg Hospital. She had
worked since 1982, on pS2/TFF1, a marker for
breast cancer hormonodependence. In 1990,
the team demonstrated the role of Matrix
Metalloproteinase 11 (MMP11), a paracrin
factor synthesized by normal stromal cells
into the tumor. The same year, Catherine went
to the Dana-Farber Cancer Institute in Boston,
US for a post-doc position. She focused on
a tumor suppressor for breast cancer and
used subtractive hybridization screening. In
1993, she returned to Marie-Christine’s team
and applied this technology to patient tumor
biopsies.
Currently, they lead a team together at
the IGBMC and are interested in tumor
development and progression. n
2
51
highlights
• Retinoic acid induces the rapid activation of
the p38MAPK/MSK1 pathway through non
genomic effects. Subsequently, RARs become
phosphorylated at two residues through a coordinated cascade starting with the phosphorylation by MSK1 of a serine located in the ligandbinding domain. This phosphorylation increases
the ability of RARs to interact with the cdk7/cyclinH subcomplex of TFIIH with a downstream
consequence on the phosphorylation of a serine
located in an N-terminal proline-rich motif.
1
probing complexity
We work at the interface of cellular and molecular biology
focusing on retinoic acid, the active metabolite of vitamin
A, which controls cell proliferation and differentiation
through nuclear receptors. These receptors, RARs, work
as ligand-dependent transcriptional regulators but complexity came with the finding that RARs are targets for
post-translational modifications such as phosphorylations,
which turned out to be crucial for their transcriptional activity.
Our goal is to dissect the mechanisms and consequences of
RARs phosphorylation. We analyze how phosphorylation
controls the dynamics of RAR-target genes’ transcription.
We also focus on how phosphorylation interferes with ubiquitination for RARs transcriptional activity and degradation. Given that many tumoral processes are characterized
by aberrant kinase signaling pathways, we are engaged in a
large analysis of RARs phosphorylation in cancer cell lines
and tumor samples in correlation with their sensitivity to
retinoic acid.
The final important focus of our studies is to define how
phosphorylation controls the activity of RARs during cell
differentiation and embryonic development.<
shaping the future
Nuclear retinoic acid receptors phosphorylation
and cross-talk with signaling pathways
The importance of RARs phosphorylation stands in contrast
to the difficulty of detecting this modification and of
analyzing its biological significance. The challenge in the next
years to come is to combine cellular, molecular, biophysical
and computer modeling approaches to investigate :
● the phosphorylation state of RARs in different cell types.
The purpose is to correlate aberrant RAR phosphorylation
states with cancer
● the conformational changes induced by phosphorylation
in order to predict changes in the interaction of RARs with
protein partners or DNA
● the role of RARs phosphorylation during development by
using induced pluripotent stem cells obtained from mouse
embryonic fibroblasts and reexpressing RARs mutated at
the phosphorylation sites in a RAR null background. <
Cécile Rochette-Egly
From cellular
to molecular biology
• Phosphorylation regulates the transcription of
RAR-target genes via the control of RARs recruitment to gene promoters and via RARs ubiquitination and degradation by the proteasome.
• New coregulators with SH3 domains and interacting
with the N-terminal proline-rich motif have been cloned
and shown to interact with RARs in a phosphorylationdependent manner.
Bruck N, Vitoux D, Ferry C, Duong V, Bauer A, de Thé
H, Rochette-Egly C. A coordinated phosphorylation
cascade initiated by p38MAPK/MSK1 directs RARalpha to target promoters.
EMBO J. 28(1):34-47. (2009).
• RARs phosphorylation is altered in several breast cancer
cells that are resistant to the antiproliferative effect of retinoic acid. n
Bour G, Lalevée S, Rochette-Egly C. Protein kinases
and the proteasome join in the combinatorial control
of transcription by nuclear retinoic acid receptors.
Trends Cell Biol. 17(6):302-9. (2007).
1- Nuclear localization of RARalpha
(green) in breast cancer cells.
2- Aberrant cytosolic localization of
RARalpha (green) in stromal fibroblasts
from invasive breast carcinoma.
Gaillard E, Bruck N, Brelivet Y, Bour G, Lalevée S,
Bauer A, Poch O, Moras D, Rochette-Egly C. Phosphorylation by PKA potentiates retinoic acid receptor
alpha activity by means of increasing interaction with
and phosphorylation by cyclin H/cdk7.
Proc Natl Acad Sci U S A.103(25):9548-53. (2006).
After earning a diploma in Pharmacy and
completing her residency in Paris, Cécile
Rochette-Egly obtained a PhD in Cell
Biology in Villejuif in 1978. At that time her
work dealt with cell signaling and cyclic
nucleotide second messengers. In 1979 she
joined Inserm as a Research Associate and
in 1980 she obtained a Honorary Doctorate
of Science on the role of cyclic nucleotide
in biological functions. In 1988, she joined
Pierre Chambon’s team in Strasbourg to
work on nuclear retinoic acid receptors
(RARs).
Since 1992 she is an INSERM Research
Director and in 1994 she moved to the
IGBMC and became the leader of her own
team on RARs phosphorylation. She showed
that retinoic acid receptors are targets for
phosphorylation cascades which turned out
to be crucial for their activity. n
2
53
highlights
• A new cellular compartment: We have identified
and characterized new cytoplasmic structures
involved in mRNA decay that contain, among
others, decapping enzymes.
• Hidden transcripts: We have identified a new
poly(A) polymerase and have shown that it is
involved in a RNA quality control pathway that
targets a new type of transcript: Cryptic Unstable Transcripts (CUTs).
1
probing complexity
The control of gene expression allows cells and organisms
to adapt to changing conditions and to drive internal Programmes such as cell cycle or development. Gene expression
is an intricate multistep pathway in eukaryotes, allowing for
multiple layers of regulations, but this process is also error
prone. Thus, potentially deleterious aberrant transcripts need
to be rapidly eliminated.
Our goal is to understand how the RNA decay process
contributes both to regulated gene expression and to the elimination of defective transcripts. Several pathways implicated in the degradation of eukaryotic RNAs have been identified. If several or most of the enzymes involved in this process
are now known, the mechanisms activating specific enzymes
in defined conditions remain to be elucidated. For example,
we would like to decipher the mechanisms allowing cells to
discriminate bona fide mRNA from defective transcripts or
how the stability of specific RNA is regulated. This requires
the characterization of the various protein complexes implicated in RNA decay and of their dynamic interactions. Additional complexity arises from the connection of mRNA decay to other cellular processes. Integrated approaches are thus
necessary to decipher globally the contribution of mRNA
decay to gene expression control.<
shaping the future
Protein networks and complexes regulating
eukaryotic mRNA decay
RNA decay remains a complex and poorly understood
process involved both in the constant renewal of mRNA
used for protein synthesis and in the elimination of defective
transcripts. Enzymes involved in this process act in general
turnover and RNA quality control pathways. We will now
concentrate on the mechanism leading to activation of
these factors.
Using mechanistic, cellular and integrated approaches,
several lines of research will be pursued using both yeast
and mammalian cells as model systems: (i) How do cells
distinguish aberrant from functional RNAs? (ii) How is
mRNA decay regulated? (iii) Can we decipher the dynamic
protein interaction networks underlying RNA decay? (iv)
How is RNA decay integrated at the cellular level (e.g., with
transcription and translation)? <
Bertrand Seraphin
• Protein complexes mediating RNA decay: Using
a combination of approaches including innovative protein purification and mass spectrometry
strategies, we have contributed to the characterization of the organization, structure, function
and activities of various protein complexes involved in eukaryotic mRNA decay such as the
And RNA disappears
exosome and the Exon Junction Complex (EJC) core.
Lebreton A, Tomecki R, Dziembowski A, Séraphin
B. Endonucleolytic RNA cleavage by a eukaryotic
exosome. Nature. 456:993-996. (2008).
• Regulating gene expression at a post-transcriptional level:
We have characterized yeast and human deadenylases and
some of their regulators to understand how this process
is integrated in the cell and contributes to the control of
protein production. n
Mauxion F, Faux C, Séraphin B. The BTG2 protein is a
general activator of mRNA deadenylation.
EMBO J. 27:1039-1048. (2008).
1- mRNA decay bodies (Dcp bodies
or P bodies) in HEK293 cells: red
immunodetection of hDcp1a; blue:
DNA/nuclei.
2- Monitoring the effect of mRNA
decay factors on translation termination: different yeast mutants harboring
a reporter for stop codon readthrough
turn from white to red (right), or grow
better (left), on appropriate media.
Dziembowski A, Lorentzen E, Conti E, Séraphin B.
A single subunit, Dis3, is essentially responsible for
yeast exosome core activity.
Nat Struct Mol Biol. 14:15-22. (2007).
Wyers F, Rougemaille M, Badis G, Rousselle JC,
Dufour ME, Boulay J, Régnault B, Devaux F, Namane
A, Séraphin B, Libri D, Jacquier A. Cryptic pol II
transcripts are degraded by a nuclear quality control
pathway involving a new poly(A) polymerase.
Cell. 121:725-737. (2005).
After studying at the ENS, Bertrand Seraphin
obtained his PhD in 1988 at Curie Institute
in Orsay on mitochondrial intron splicing,
particularly on the role of a protein from
a new family, the DEAD Boxes. From 1987
to 1989, while he was a post-doctorate at
Brandeis University in Boston, USA with
Professor Rosbash, he studied yeast nuclear
splicing and brought to light new splicing
complexes (commitment complexes). In
1991, he joined the EMBL, with Iain Mattaj
and then became a team leader. His work on
characterization of splicing complexes (Sm
proteins, snRNP U1 et U6, etc.) brought him
to develop a protein complexes purification
strategy, the “Tandem Affinity Purification”
(TAP method). In 2000, he integrated the
CGM (Gif-sur-Yvette) where he studied RNA
decay, discovering new enzymes, a new cellular compartment and new nonannotated
transcripts: CUTs (Cryptic Unstable Transcripts). His research has been continuing at
the IGBMC since 2009. n
2
55
highlights
• 3D tracking of the motion of DSBs in living
cells has shown that free chromosome ends have
limited motion and they are unable to roam the
cell nucleus.
• The repair protein Ku80 is involved in keeping the free chromosome ends aligned.
• Analysis of translocation partners of unrepaired chromosome breaks has shown that
they preferentially undergo translocations with
neighboring chromosomes.
1
probing complexity
Each cell in the human body receives thousands of DNA
lesions per day. DNA lesions can interfere with genome replication and transcription, and if they are not repaired or
are repaired incorrectly, they lead to mutations that may
threaten cell viability. The most deleterious DNA breaks are
the Double Strand Breaks (DSBs) because unfaithful repair
can lead to the formation of cancerous chromosomal translocations. It is poorly understood why translocations between
chromosomes recur at specific break points in the genome
and even less is known about how ends from different DSBs
meet in the cell nucleus. It was recently shown that broken
chromosome ends are positionally stable and unable to roam
the cell nucleus and that unrepaired DSBs preferentially undergo translocations with neighboring chromosomes. In our
group we are using a unique cell system to induce DSB at a
specific chromosomal location and to follow the fate of damaged DNA in living cells in real time. Our goal is to investigate the dynamics of DSBs in relation to the surrounding
chromatin structure and nuclear architecture and to test how
this is related to their repair and their involvement in the
formation of chromosomal translocations.<
shaping the future
Cell Biology
of genome integrity
We are interested in the role of chromatin structure and
nuclear architecture in the repair of Double Strand Breaks
and the formation of chromosomal translocations. Our
current objectives are:
● to visualize the dynamics of DNA damage response and
the formation of chromosomal translocations in living cells.
● to study the role of chromatin structure and nuclear
architecture in DNA damage response and formation of
chromosomal translocations.
● to identify novel chromatin related proteins that are
involved in DNA repair.
The insights gained from these in vivo studies will have
a significant impact on our understanding of how the
organization of repair in the context of a highly compacted
chromatin and compartmentalized nucleus contributes to
prevention of genomic instability. <
Evi Soutoglou
Nuclear architecture
and chromatin structure
in DNA repair
• DNA repair factors are spreading around
the DSBs and they form microscopically visible
structures known as repair foci. Mimicking of
repair foci by immobilization of a single repair
factor to chromatin has shed light into their critical role in the activation and the amplification
of the DNA damage response.
• siRNA screen in mammalian cells revealed several chromatin related proteins that are involved in DNA damage
response and DNA repair (unpublished). n
DNA repair: easy to visualize, difficult to elucidate.
Nagy Z, Soutoglou E.
Trends Cell Biol. 19(11):617-29. (2009).
Evi Soutoglou obtained her PhD at
the Institute of Molecular Biology and
Biotechnology (IMBB) in Crete, (Greece) on
transcription regulation in 2002. She then
spent a short post-doc with Laszlo Tora’s
group at the IGBMC. In 2003, she joined the
National Institute of Health (NIH) and worked
with Tom Misteli on nuclear architecture
and chromatin dynamics in DNA repair. Evi
created a system to visualize DNA double
strand breaks in living cells. In 2009, she
returned to the IGBMC to set up her own
team. n
The emerging role of nuclear architecture in DNA repair
and genome maintenance. Misteli T, Soutoglou E.
Nat Rev Mol Cell Biol. 10(4):243-54. (2009).
1- Chromatin decondensation induced
by tethering of the repair factor MDC1
shown in 3D.
2- Dual color FISH with chromosome
3 (green) and chromosome 19 (red)
paint probes in NIH 3T3 cells.
Activation of the cellular DNA damage response in
the absence of DNA lesions. Soutoglou E, Misteli T.
Science. 320(5882):1507-10. (2008).
Positional stability of single double-strand breaks in
mammalian cells. Soutoglou E, Dorn JF, Sengupta K,
Jasin M, Nussenzweig A, Ried T, Danuser G, Misteli T.
Nat Cell Biol. 9(6):675-82. (2007).
2
57
highlights
• We identified and characterized several novel
subunits of the human and Drosophila general transcription factor, TFIID. We described that different
TFIID complexes exist in the cells and that these
complexes regulate transcription differentially.
• We discovered and characterized novel TATA
binding protein (TBP)-like factors, such as TLF (also
called TRF2) and TBP2 (also called TRF3) and our
work suggested that that these factors play a role as
cell-type specific initiation factors.
shaping the future
Chromatin modifications and regulation of
gene expression during differentiation
We characterize the activities of several mammalian
transcription factor complexes to get more insights in
their function during cell growth and differentiation. The
combination of different multidisciplinary approaches
(i.e. ChIP-seq, proteomic, cell biology, imaging, and
bioinformatics) will lead to the identification of genes and
pathways regulated by these complexes and their function
in mammalian cell differentiation and development.
Our studies will also help to find ways to interfere with
the action of these transcription factors, when needed
in pathological situations. We anticipate that the results
of our research will have a major impact on the field and
will potentially lead to a paradigm for contemporary
metazoan transcription regulation and multiprotein complex
research.<
LÁszlÓ Tora
Studying transcription
factors and coactivators
• We demonstrated a tight coupling between initiation of transcription and the 3’ maturation of premRNAs.
1
probing complexity
Our main research interest is to study how specific protein
coding genes are turned on and off in the nucleus of a given
cell, during growth, differentiation and development. We use
biochemical, genetic, cell biology, imaging and structural approaches to study the problem of control of gene expression
in different metazoan organisms. The lab’s research is broadly
centred on three different axes, which all aim to better understand RNA polymerase II transcription: (i) the role of different proteins belonging in the TATA box binding protein
(TBPs) protein family, (ii) the role of TBP-associated factor
(TAF)-containing complexes (i.e. TFIID and SAGA); and
(iii) the role of histone acetyl transferase (HAT)-containing
chromatin remodelling coactivator complexes (i.e. SAGA
and ATAC) in gene regulation. Our current and planned activities aim to better understand gene regulatory processes in
different cellular systems and also during the development of
intact vertebrate organisms. Our work on the different transcription factors also contributes to a better understanding of
how a polyglutamine expansion in a SAGA subunit causes a
neurodegenerative disorder (i.e. Spinocerebellar ataxia type
7) or how the deregulation of the deubiquitination function
of human SAGA causes metastatic cancers.<
• We discovered and characterized a new human
histone acetyl transferase-containing coactivator
Zhao Y., Lang G., Ito S., Bonnet J., Metzger E., Sawatsubashi S., Suzuki E., Le Guezennec X., Stunnenberg
H.G., Aleksey Krasnov, Sofia G. Georgieva, Schüle R.,
Takeyama K.-I., Kato S, Tora L.* and Devys D.* A TFTC/
STAGA module mediates histone H2B deubiquitination,
nuclear receptor activation and counteracts heterochromatin silencing. Molecular Cell. 29:92-101. (2008).
complex (called TFTC or SAGA) playing a role in chromatin remodelling. Motivated to explore the importance
of this factor in diseases, our
findings have helped to uncover the mechanisms by which
a polyglutamine expansion in
a subunit of SAGA leads to
photoreceptor dysfunction in
a mouse model of SCA7. n
Kurshakova M.M., Krasnov A.N., Kopytova D.,
Shidlovskii Y.V., Nikolenko J.V., Nabirochkina E.N.,
Spehner D., Schultz P., Tora L.* and Georgieva S.G.*
SAGA and a novel Drosophila export complex anchor
efficient transcription an mRNA export to NPC.
EMBO J. 26:4956-4965. (2007).
Helmlinger D., Hardy S., Abou-Sleymane G., Eberlin
A., Bowman A., Gansmüller A., Picaud S., Zoghbi
H.Y., Trottier Y., Tora L.* and Devys D.* GlutamineExpanded Ataxin-7 Alters TFTC/STAGA Recruitment
and Chromatin Structure Leading to Photoreceptor
Dysfunction. Plos Biology. 4(3):0432-0445. (2006).
2
1- Detection of specific subunits of a histone
acetyltransferase complex (ATAC) by
immuno fluorescence in mouse cells by using
antibodies against Ada2a (red) and Ada3
(green). Merged images together with DNA
(blue) are shown in the left panels.
2- Heat map representing density matrix after
k-means clustering of genome wide transcription factor binding sites. Binding densities of
four histone acetyl transferases (PCAF, CBP,
MOF and TIP60) were clustered according
to p300 binding loci.
After graduating from the Eötvös Lorànd
University in Budapest with a PhD in
Biochemistry and Molecular Biology in 1985,
Laszlo Tora did his post-doc in Strasbourg to
study nuclear receptors, first with M. Bellard
and then with Pierre Chambon. Between 1988
and 1989, he participated in the discovery that
estrogen and progesterone nuclear receptors
have two distinct activation domains. Since
1993, he has led his own team at the IGBMC
and has worked on transcription regulation
mechanisms. In 1994, his team identified
and characterized three subunits of the TFIID
transcription factor and showed that different
TFIID complexes have a different regulation
activity. In 1997, Laszlo demonstrated the
coupling between transcription initiation and
polyadenylation. He then found TFTC and
proved its role in chromatin remodeling in
1998. In 2000 and 2004, he discovered and
characterized new TBP-like factors. n
59
highlights
• From functional characterization, therapeutic target validation and high throughput
screening, we have identified a compound, XRP44X, which inhibits the Ras oncogene – Net
transcription factor signalling pathway (Wasylyk
et al., 2008) and metastasis in pre-clinical cancer
models (patent application).
1
probing complexity
Our mission is to create knowledge that could be beneficial
for the treatment of cancer in the near future. We are interested in studying the cancer-related functions of novel genes
that we have identified, as well as known oncogenes and tumour suppressors. This involves studying their mechanisms
of action, validating them as targets for high throughput
screens (HTS), and establishing their usefulness as markers
for diagnosis and prognosis.
We are studying several types of human cancer, including
head and neck squamous cell carcinoma (HNSCC) and
prostate cancer (CaP). HNSCC is particularly frequent in
France; it accounts for 12% of deaths by cancer in males,
and 5-year survival is about 30%. Prostate cancer is now the
most frequent cancer in men (350,000, 20% in Europe).
Treatment of primary tumours leads to initial remission that
later progress to invasive growth and metastasis. The reasons
for relapse are not known and are the topic of many ongoing
research projects. There is an urgent need to understand the
biological mechanisms of cancer progression, in order to
develop new therapies and markers that could be used to
successfully treat cancer patients.<
• We have characterized a novel gene, TTLL12,
whose expression increases with prostate cancer
progression (Wasylyk et al., 2010), validated it
as a target for HTS (patent application), developed an assay, and identified hits in a screen of
a worldwide diversity set of compounds.
shaping the future
Molecular and cellular
biology of cancer
We aim to:
● complete the characterization of XRP44X in pre-clinical
cancer models of metastasis and characterize the novel
signaling pathway that is affected.
● use the hits from the screen of the world diversity set
of compounds to develop compounds that will be useful
to explore TTLL12 functions and establish whether they are
effective for tumour therapy.
● study the functions of the genes in the gene-expression
signature of future metastasis and use them to develop
new treatments (Ano1).
● validate our model for intimate crosstalk between
HIF1alpha and Net, and use this knowledge to develop
treatments for hypoxia related diseases.<
Biology applied to cancer
• Gene expression signatures have been identified that distinguish subgroups of HNSCC associated with poor and good prognosis (Rickman
et al., 2008 and Jung et al., 2010, respectively).
• We have postulated a model for intimate crosstalk
between signaling pathways involving the master regulator
of the hypoxic response, HIF1alpha, and the transcription
factor Net (Gross et al., 2008; Serchov et al., 2010). n n
Wasylyk C, Zambrano A, Zhao C, Brants J, Abecassis
J, Schalken JA, Rogatsch H, Schaefer G, Pycha A,
Klocker H, Wasylyk B. Tubulin tyrosine ligase like 12,
link to prostate cancer through tubulin post-translational modification and chromosome ploidy.
Int J Cancer. (2010).
1 + 2 - Colocalisation of TTLL12
with filaments. TTLL12 (red, 1 & 2)
colocalises with vimentin (green, 1)
and microtubules (not shown), which
may to related to its effects on tubulin
modification, mitotic duration,
chromosome number instability and
cancer.
Jung A, Briolat J, Millon R, de Reyniès A, Rickman
D, Thomas E, Abecassis J, Clavel C and Wasylyk B.
Biological and clinical relevance of transcriptionnally
active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma.
Int J Cancer. 126(8):1882-94. (2010).
Wasylyk C, Zheng H, Multon MC, Debussche L and
Wasylyk B. Inhibition of the Ras-Net (Elk-3) pathway
and tumour growth in vivo by a novel pyrazole.
Cancer Res. 68(5):1275-83. (2008).
Bohdan Wasylyk
After obtaining a PhD in Biochemistry at
Glasgow University on DNA structure and
DNA interactions with RNA polymerase during
transcription, Bohdan Wasylyk was awarded
an EMBO Fellowship to join Pierre Chambon’s
laboratory in Strasbourg in 1975. He worked on
eukaryotic RNA polymerases and regulation
of transcription by nucleosomes and promoter
elements (TATA sequences and enhancers).
Bohdan was appointed CNRS Research
Associate and focused his work on the
regulation of gene expression by oncogenes
(Ras, MDM2, etc.) and tumour suppressors
(p53). He has focused on particular cancers,
including head and neck squamous cell
carcinoma and prostate cancer. Bohdan
participated in HTS’s for small molecule
therapeutics that target p53, Ras and TTLL12.
This has resulted notably in the identification
of XRP44X. n
2
61
How the architecture of biological systems sheds light on their function
" We aim at determining biomolecular structures at the atomic
level to position these molecules in functional complexes and to analyze
or predict their motion. " P. Schultz
Our Programme aims at understanding the
mechanisms of cellular processes by correlating the structural and the functional
properties of their macromolecular components. The regulation of gene expression in
a broad sense, ranging from transcription
regulation, chromatin structure, DNA topology to messenger RNA translation, forms
the core scientific activity of our community.
These fundamental biological processes are
of major importance for public health and
the research conducted. These impact on
our understanding of human diseases, drug
target identification and drug optimization,
for example, the studies on nuclear hormone
receptors and their co-regulators have strong
implications for cancer, osteoporosis, obesity
and type II diabetes.
INTEGRATED
STRUCTURAL BIOLOGY
The research teams are highly interconnected
since multiple experimental approaches have
to be combined to address challenging projects. Highly specialized structure determination methods such as X-ray and neutron
• The structures of eukaryotic transcription factors and
co activators illuminate the mechanisms of transcriptional regulation and explain the action of hormones.
• The ribosome machinery, determined in different
functional states, explains the translation regulation
pathways and the inhibition strategies of antibiotics.
diffraction and diffusion, NMR, cryo electron microscopy and more recently, imaging
are associated with multi parametric data
analysis and modeling approaches developed
in the bio-computing teams. Recombinant
and endogenous biological sample production, purification and biophysical characterization are key players in
the structure determination
pipeline supported and de8 Groups
veloped in our Programme.
29 Staff scientists
24 Postdoctoral fellows
The vision of structural biology for the next years will
21 PhD students
pave the way towards inte25 Engineers/Technicians
grated cellular structural biology with the aim of addres1 Assistant
sing multifactorial effects in
the personalized context of a
unique human being. Our contribution to
this evolution translates as the multi-resolution analysis of large complexes from their
atomic structure to their in-cell distribution
and interactome, in the investigation of the
dynamics of biological processes at all levels
of complexity and in hybrid data integration
for knowledge production. In line with this
commitment, the future Center of Integrated Biology will host one of the two French
nodes of INSTRUCT, the European infrastructure for integrative structural biology. n
• Chromatin and DNA modifying enzymes are drug targets for human diseases. Our studies contribute to the
better understanding of drug action and guide rational
drug design.
• Integrative bioinformatics and genomics combine
evolutionary, ontologic and omics data to extract knowledge.
• We are committed to the development of new conceptual methodologies and novel modes of instrumentation
to lead us towards tomorrow’s discoveries.
63
highlights
• PRMTs: Co-activator-associated arginine
methyltransferase 1 (CARM1 also known as
PRMT4) methylates a large variety of proteins
which are vital to gene expression.
Our high resolution structures of several isolated
modules of CARM1 have highlighted molecular switches that expand our understanding of
how CARM1 regulates its biological activities.
Furthermore, complementary functional studies
have provided clues on the mode of binding of
arginine-containing substrate or product peptides to CARM1.
1
probing complexity
Chromatin structure is a major barrier to all nuclear
processes and its modulation is essential for correct cell
growth. There is now clear evidence that defects in chromatin modulation are responsible for a wide range of diseases, including cancer. Epigenetic modifications have
a large impact on chromatin structure, acting in synergy
with ATP-dependent remodelers, histone variants and histone chaperones to regulate nuclear mechanisms. By combining state-of-the-art biochemical and crystallographic
techniques, we aim to understand chromatin remodeling
at the molecular level. Three main targets are the current
focus of our research: protein arginine methyltransferases
(PRMTs), histone chaperones and histone deacetylases
(HDACs). Furthermore, we are also developing structurebased rational approaches to characterize small molecule
modulators of the biological activities of our targets since
they are frequently involved in human diseases.
Our team also participates in collaborative research on several related projects which require our specific expertise.
Present collaborations concern the structural studies of
complexes of cancer-related targets such as the Translationally Controlled Tumor Protein (TCTP) and the mRNA
of human histone H4.<
shaping the future
Structural biology
of epigenetic targets
Most epigenetic players involved in the regulation of gene
expression are multi-protein complexes. We are addressing
the challenge of characterizing in molecular terms the biologically relevant complexes (that contain our targets) by
developing a structural biology-based approach, integrating
identification, production, purification, biophysical characterization and structure determination.
Combining multi-resolution structural analysis with biological-functional studies will allow us to gain a better understanding on how these complexes function in a biological
context. A structure-based approach will also be used to
discover, generate and validate novel epigenetic regulators,
since the availability of such compounds is at the heart of
new therapies against the expanding number of diseases
shown to depend on epigenetic mechanisms.
<
Jean Cavarelli
Understanding biology at
the atomic scale
• Histone chaperones: The structure of the C-terminal part of Spt6 revealed a non-canonical tandem SH2 domain essential for Spt6 interaction
with the hyperphosphorylated RNA Polymerase
II CTD. Furthermore, structural characterization of the interaction between Spt6 and Iws1
leads to specific mutants affecting yeast viability and we
are deciphering the role of each partner in vivo.
Bieniossek, C., Nie, Y., Frey, D., Olieric, N., Schaffitzel,
C., Collinson, I., Romier, C., Berger, P., Richmond, T.J.,
Steinmetz, M.O., Berger I. Automated unrestricted
multigene recombineering for multiprotein complex
production. Nat. Methods. 6:447-450. (2009).
• Technological developments: Besides our scientific commitments, our development of multi-expression tools and
our structural and crystallographic expertise is essential to
tackle our internal and collaborative projects. n
Troffer-Charlier N., Cura V., Hassenboehler P. , Moras
D. and Cavarelli, J., Functional insights from structures
of coactivator-associated arginine methyltransferase 1
domains. EMBO J. 26(20):4391-4401. (2007).
1- Structure of the PRMT catalytic
domain of CARM1with bound SAH at
2.2 Å. Two monomers are shown here
(residues 140-480 of mouse CARM1)
building an active dimer.
2- Model of the Spt6/Iws1 complex.
Romier, C., James, N., Birck, C., Cavarelli, J., Vivarès,
C., Collart, M.A., Moras, D. Crystal structure, biochemical and genetic characterization of yeast and E.
cuniculi TAFII5 N-terminal domain: implications for
TFIID assembly. J. Mol. Biol. 368:1292-1306. (2007).
Klein, F.A.C., Atkinson, R.A., Potier, N., Moras, D. and
Cavarelli, J. Biochemical and NMR mapping of the
interface between CREB-binding protein and ligand
binding domains of nuclear receptors: beyond the
LXXLL motif, J. Biol. Chem. 280:5682-5692. (2005).
Educated in chemistry, Jean Cavarelli changed his focus to biology and obtained a PhD
in Structural Biophysics at the University of
Strasbourg with Dino Moras’s team, focusing on crystallographic studies of proteinnucleic acid complexes (1987). He spent two
years as a post-doctoral fellow at Purdue
University in West-Lafayette, Indiana, USA
where he solved the structure of an insect
virus in 1989. Beginning as Associate Professor and then Full Professor in 1996 at the
University of Strasbourg, he worked for a
long time on aminoacyl-tRNA synthetasecomplexes before focusing on epigenetics
targets, notably PRMTs. He has participated
in several collaborative projects on proteins
related to human diseases, nuclear receptor
coactivators and transcription factors. The
research of his team is currently focused
on epigenetic targets. He is also strongly
involved in teaching, leading several Programmes in structural biology and structural
bioinformatics at the University. n
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65
highlights
• Identification of dynamically coupled amino
acids in the I-domain of the integrin LFA-1
uncovers an allosteric network that participates
in the complex signal transduction mechanism
of integrins. The calculations show that active
compounds can interfere with this dynamically
coupled network and result in the perturbation
of signal transmission.
1
probing complexity
Molecular interactions that occur between biological molecules and their ligands are underlying the vast array of
processes that take place in a living organism are. We are
trying to understand and characterize the molecular recognition processes using computational approaches that
permit the characterization of the molecule-level dynamics
and aim to understand the thermodynamics of molecular recognition processes and to further comprehend the
structural and dynamic consequences of such interactions.
For example, we are trying to elucidate how molecular
signals are transmitted in biomolecular systems. Recent
applications focus on the nuclear receptor superfamily of
ligand-activated transcription factors which play a primordial role in complex processes such as cell differentiation,
development, and homeostasis. We study the interplay
between ligand binding, structural changes and allostery
in these receptors. Other proteins under study include
the integrin cell adhesion proteins. These projects are developed in collaboration with experimental groups at the
IGBMC and elsewhere. These studies also provide important information that can be exploited in rational drug
design projects that are developed at the interface of molecular biology, biophysics and organic synthesis groups.<
shaping the future
Biocomputing
Our goal will be to use computational tools to study structure-function relationships of macromolecular complexes
implicated in transcription regulation, in collaboration with
other IGBMC teams involved in structural biology, experimental biophysics and bioinformatics.
We will use atomic-level simulation studies of nuclear receptors to further our understanding of the molecular
mechanisms of ligand recognition and allosteric communication in these proteins. Specifically, we shall study the
role of phosphorylation-mediated structural and dynamical
changes, the associated molecular mechanisms and implications for allosteric communication.
We will also work towards the modeling of large macromolecular assemblies using hybrid computational and experimental methods. <
Annick Dejaegere
Computation for biology
• A dynamically coupled amino acid network
is identified in the ligand-binding domain of
human peroxisome proliferator-activated receptor-g nuclear receptor protein. This network was
shown to be influenced by the presence of agonist molecules.
• Free energy decomposition of protein-protein and protein-ligand complexes provides insight into the molecular
mechanisms of supramolecular assembly and pinpoints highlights interactions that can be used as starting points for
drug design. n
G. Moroy, A. Dejaegere, R.H. Stote, “Molecular basis
for BH3 domain recognition in the BCL-2 protein
family: Identification of conserved hot-spot interactions”. J. Biol. Chem. 284:17499-17511. (2009).
C. Browning, E. Martin, C. Loch, JM Wurtz, D. Moras, R.H. Stote, A.P. Dejaegere, I.M.L. Billas, “Critical
Role of Desolvation in the binding of 20-Hydroxyecdysone to the ecdysone receptor”.
J. Biol. Chem. 282:32924-32934. (2007).
1- Representation of functional motions
in the I-domain of the integrin LFA-1.
2- Representation of the dimer of the
ligand binding domains of the nuclear
receptors RAR and RXR. Analysis of the
stabilizing amino acids at the dimer interface shows a conserved motif (highlighted
in surface representation).
T. Gaillard, E. Martin, E. San Sebastian, F. P. Cossio,
X. Lopez, A. Dejaegere, R. H. Stote, “Comparative
Normal Mode Analysis of LFA-1 Integrin I-domains”
J. Mol. Biol. 374:231-249. (2007).
V. Lafont, M. Schaefer, R. H. Stote, D. Altschuh, A.
Dejaegere « Protein-protein recognition and interaction hot spots in an antigen-antibody complex: free
energy decomposition identifies “efficient amino
acids”. » Proteins. 67:418-434. (2007).
Annick Dejaegere obtained a PhD in Physical
Chemistry at the Free University of Brussels
in Belgium. In 1989, she studied interactions
in aromatic molecules with Jacques Reisse.
She joined Martin Karplus’ team for her
post-doc at Harvard University, USA. She
worked on the reactivity of phosphates and
proposed an original interpretation on the
role of solvation in the reactivity of these
molecules.
In 1993, she joined the NMR group of JeanFrançois Lefèvre at the (Louis-Pasteur) University of Strasbourg, and developed predictive models of chemical shift for NMR
structure determination. In 1995, her work
highlighted original links between DNA
backbone structure and chemical shift.
In 2002, she joined IGBMC where she leads
a team dedicated to the computational study
of protein complexes. n
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67
highlights
• We have elucidated the solution structure of
several domains of transcription factor TFIIH
and have studied their interaction properties. In
particular, we have shown that the self-association properties of p8, are closely linked to trichothiodystrophy.
shaping the future
Biomolecular
Nuclear Magnetic Resonance
The availability of a new 700 MHz spectrometer equipped
with a high sensitivity probe opens new perspectives for
the group. Efforts to describe disordered and functionally
important regions of proteins will be continued. Particular
emphasis will be put on the study of N-terminal regions of
several nuclear receptors, aiming at understanding the rules
that govern their evolution.
Efforts will also be devoted to study molecular interactions
within large complexes such as nucleosomes or within cellular environments.<
• The solution structure of the C-terminal zinc
finger domain of the oncoprotein E6 was elucidated. The structure displays a novel fold and
suggests a model of interaction with PDZ domains.
1
probing complexity
NMR spectroscopy provides invaluable insights into the
structural and dynamical features of biomolecular systems. We are taking advantage of NMR, combined with
other structural biology methods, to investigate molecular
properties that are important to achieve a given biological
function. Recent topics which have been addressed by the
group include the study of several structural domains of
transcription factors such as TFIIH and SAGA.
The group is also involved in the study of the Human
Papilloma Virus E6 protein and its interaction with host
PDZ domains. Often, the molecular plasticity of proteins
is crucial for their function, as illustrated by the self-association properties of p8, the smallest subunit of TFIIH or
by the role of flanking regions of PDZ domains in protein-peptide interactions. Recently, novel experimental
and theoretical tools have been developed to study the
disordered states of proteins that are involved in signaling
mechanisms. These tools are currently used to study AB
domains of nuclear receptors such as RARg and to describe their modification upon phosphorylation.<
Bruno Kieffer
Understanding the intimate
nature of proteins
• Two homologous zinc finger domains of the
Deubiquitination complex of SAGA were studied. Despite a common zinc binding motif, the
two domains exhibited distinct secondary structures and functional properties. In particular, it
was found that the SCA7 zinc finger of ATXN7
protein was able to bind nucleosomes with high affinity.
• The concept of fractal dimension has been suggested as a
functionally relevant property to describe disordered segments of proteins. n
Augé S, Schmit PO, Crutchfield CA, Islam MT, Harris
DJ, Durand E, Clemancey M, Quoineaud AA, Lancelin JM, Prigent Y, Taulelle F, Delsuc MA. NMR measure of translational diffusion and fractal dimension.
Application to molecular mass measurement.
J Phys Chem B. 113:1914-1918. (2009).
Vitorino M., Coin F., Zlobinskaya O., Atkinson A.R.,
Moras D., Egly J.-M., Poterszman A., Kieffer B. Solution structure and self-association properties of the
p8 TFIIH subunit responsible for trichothiodystrophy.
J Mol Biol. 368(2):473-480. (2007).
1- Structure of the TFIIH MAT1
RING domain illustrating the dialog
between structure and sequence
2- Structure of the TFIIH p8 subunit and the corresponding 1H-15N
HSQC spectrum
Nominé Y., Masson M., Charbonnier S., Zanier K.,
Ristriani T., Deryckère F., Weiss E., Orfanoudakis G.,
Kieffer B., Travé G. Structural and functional analysis
of papillomavirus E6 oncoprotein: New insights in
the molecular pathways of HPV-mediated pathogenesis. Molecular Cell. 21(5):665-678. (2006).
Bruno Kieffer obtained his PhD on the NMR
of proteins with Jean-François Lefèvre’s team
at Strasbourg University in 1992 and relocated to Oxford University for postdoctoral research where he resolved the first structure of
the surface protein CD59 whilst in the group
of Iain Campbell.
On his return Bruno was appointed Associate
Professor at the ESBS in Strasbourg where
besides teaching bioinformatics and biophysics, his research continued employing NMR
to study bio-molecular behavior and function.
In collaboration with the other teams of the
Institute and the IGBMC, Bruno worked on
transcription factors such as TFIIH and SAGA
and successfully determined the solution
structure of the PH domain of the TFIIH p62
sub-unit, and three years later, the 10th subunit, called p8.
Continuing his close professional relationship
with the ESBS, Bruno elucidated the structure
of the human papillomavirus E6 oncoprotein.
This research led to a registered drug patent
for medical protein control. n
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69
highlights
In the past few years we have made major progress
in the study of bacterial translation initiation complexes and human nuclear receptor complexes:
• We have trapped a 70S ribosome initiation complex with initiation factor IF2 and revealed the
conformational changes of IF2 and of the ribosome occurring upon GTP-hydrolysis.
1
probing complexity
Transcription and translation are fundamental molecular
mechanisms of gene activity regulation with profound
implications for human health. The ligand-dependent
transcriptional regulation by nuclear receptors bound to
DNA response elements involves the transient assembly
of large co-regulator complexes. These trigger chromatin
remodeling and facilitate the assembly of the general transcription machinery on the promoter of the target gene.
Gene expression is also regulated at the level of protein
synthesis, for example, by protein factors that bind to the
ribosome during the translation initiation, elongation and
termination phase.
The initiation phase is strongly regulated by factors and
also by the mRNA itself and well-characterized reaction
intermediates of the initiating ribosomal nano-machinery
are potential targets for antibiotics. Both transcription and
translation complexes represent large, transient macromolecular assemblies that we investigate by using an integrative structural biology approach with crystallography and
cryo-electron microscopy forming the core.<
shaping the future
Large complexes
involved in gene expression
In the coming years we will focus on understanding the
function of large macromolecular complexes involved
in transcription and translation. Our particular aim is to
determine the functional and structural determinants of
ligand-dependent transcription activation of nuclear receptor
and co-regulators and to address the mechanism of action
of chromatin associated complexes. We will also explore
the specific differences between the pro- and eukaryotic
protein synthesis machineries. For this, we will pursue
an integrative structural biology approach, combining,
biochemistry, bio-physics and bio-informatics, with software
developments for three-dimensional reconstruction and
multi-state image processing as well as an enhanced
integration of multi-scale tools. <
Bruno Klaholz
• We have also visualized for the first time the 30S
initiation complex in the presence of the initiator
tRNA and initiation factors IF1 and IF2, revealing
the cooperative stabilization of the tRNA in this
first event of gene decoding during protein synthesis.
Integrative biology to
understand the mechanisms
of gene expression
• We have also achieved major advances in the
study of the architecture of a full nuclear receptor
complex, while previously structural studies have
been limited to the individual ligand-binding and DNA-binding domains.
A. G. Myasnikov, A. Simonetti, S. Marzi, B. P. Klaholz.
Structure-function insights into prokaryotic and eukaryotic translation initiation.
Curr. Op. Struct. Biol. 9:300-309. (2009).
• Furthermore, we have shown the important role of mRNA
structure as illustrated by the transient ribosome-entrapment
by a folded mRNA. Notably, sequence and structure analysis
suggests the existence of a conserved site on the ribosome for
binding regulatory mRNAs. n
A. Simonetti, S. Marzi, A. G. Myasnikov, A. Fabbretti,
G. Yusupova, M. Yusupov, C. O. Gualerzi, B. P. Klaholz.
Structure of the 30S translation initiation complex.
Nature. 455:416-420. (2008).
1- Structure of the 30S translation
initiation complex.
2- The conserved site on the
ribosome for binding regulatory
mRNAs during translation preinitiation
S. Marzi, A. G. Myasnikov, A. Serganov, C. Ehresmann,
P. Romby, M. Yusupov & B. P. Klaholz. Structured
mRNAs regulate translation initiation by binding to the
platform of the ribosome. Cell. 130:1019–1031. (2007).
A. G. Myasnikov, S. Marzi, A. Simonetti, A. M. Giuliodori,
C. O. Gualerzi, G. Yusupova, M. Yusupov, B. P. Klaholz.
Conformational transition of initiation factor 2 from the
GTP- to GDP-bound state visualized on the ribosome.
Nat. Struct. Mol. Biol. 12:1145-1149. (2005).
2
Early on, Bruno Klaholz became interested
in molecular recognition. During his PhD he
worked with Dino Moras’ team at the IGBMC
and became involved in crystallography to
determine the three-dimensional structure of
nuclear receptors and to analyze their specific
interactions with pharmaceutical ligands. In
2001, he began his post-doc at Imperial College, London and extended his knowledge
to single particle cryo-electron microscopy,
allowing him to visualize the 3D structure of
molecules in their native state. At that time he
investigated the molecular function of ribosomes during termination of protein synthesis. In 2003, he returned to the IGBMC and
subsequently created his own research team
with a focus on the molecular mechanisms
that regulate gene expression. For the study
of these large complexes he favors an integrated approach using electron microscopy,
crystallography, biochemistry and bioinformatics. Through advanced image processing
and statistical analysis he also developed
approaches to separate different structural
states in a single sample. n
3
71
highlights
• The functional relevance of two mutually exclusive signature motifs of the ligand binding domain
that partition the nuclear receptor superfamily
into two classes with specific molecular pathways
is illustrated by the allosteric control of retinoic
acid receptor (RAR) activity by phosphorylation.
shaping the future
Expression
of genetic information
Three aspects of transcription regulation by nuclear hormone receptors will be investigated:
• The role of DNA in the correct positioning of the receptors
and the architecture of their complexes with cofactors.
• The molecular mechanisms that control the binding of
cofactor proteins.
• The structural aspects of NHR action at the chromatin
level. Integrative structural biology tools will be used and
developed to characterize structural and functional aspects
both in vitro and in the cell. For the vitamin D and retinoids
receptors, the investigation will be extended to the tissue
and animal model (mouse) levels.
<
• Role of the ligand and drug design: i) the work
on the insect ortholog USP of RXR provides novel insights into receptor-ligand binding evolution
and dynamics; ii) a structural water channel has
been characterized and used to design a more potent superagonist for the Vitamin D Receptor.
1
probing complexity
Our goal is to understand the molecular mechanisms that
control gene expression in human cells and animal models.
We are focusing on the study of transcriptional regulation
by nuclear hormone receptors (NHR), using integrative
structural biology approaches to decipher the structural
basis of the communication between nuclear receptors,
DNA and components of the basal transcription machinery. NHR-mediated transcription is regulated by ligands
and post-translational modifications. Understanding the
role of these factors in molecular control mechanisms (ie.
allosteric regulation of the activity), has important implications for pharmacological applications (drug design).
Today’s integrative structural biology demands multiscale structural data and their translation into functional
knowledge. We use X-ray crystallography, EM and NMR
techniques to determine structure and dynamics at different levels of detail, ranging from atomic resolution of
individual proteins or small complexes to tomographic
analysis of large particles. Macromolecular complexes can
be relatively stable (e.g. ribosomes) or transient. For the
latter, the temporal component is crucial and reconstitution of the proper sequence of events in the cell using light
microscopy tools is an essential part of our studies.<
Dino Moras
Molecular mechanisms of
gene expression
• The structural basis for understanding the role of
DNA in the spatial organization of NHR heterodimers in functional transcription complexes with
cofactors has been investigated using a combination of solution techniques. Several structures have
been determined.
• The first structure of HIV integrase in complex with DNA
and the cellular cofactor LEDGF/p75 was determined by
EM.
Michel F, Crucifix C, Granger F, Eiler S, Mouscadet JF,
Korolev S, Agapkina J, Ziganshin R, Gottikh M, Nazabal A, Emiliani S, Benarous R, Moras D, Schultz P,
Ruff M. Structural basis for HIV-1 DNA integration in
the human genome, role of the LEDGF/P75 cofactor.
EMBO J. 28:980-91. (2009).
• The X-ray structure of p8/Tfb5 in complex with another
TFIIH subunit was elucidated, providing a molecular basis
for trichothiodystrophy, a rare disease. n
Hourai S., Rodrigues L.C., Antony P., Reina-SanMartin B., Ciesielski F., Magnier B.C., Schoonjans K.,
Mourino A., Rochel, N., Moras D. Structure-based
design of a superagonist ligand for the vitamin D
nuclear receptor. Chem. Biol. 15:383-392. (2008).
1- RXR/RAR on the RARβ2 promotor
within a nucleosome..
2- The HIV-1 integrase in complex with
a cellular co-factor (LEDGF), viral and
cellular DNA.
Iwema T., Billas, I.M.L., Beck Y., Bonneton F., Nierengarten H., Chaumot A., Richards G., Laudet V., Moras
D. Structural and functional characterization of a
novel type of ligand-independent RXR-USP receptor.
EMBO J. 26:3770-3782. (2007)
Yusupova G., Jenner L., Rees B., Moras D., Yusupov
M. Structural Basis for messenger RNA movement
on the ribosome. Nature. 444:391-394. (2006)
DIno Moras graduated with a degree in Chemistry, then went on to study structural biology as a post-doctorate fellow with Michael
Rossmann at Purdue University, West Lafayette, Indiana, USA. Notably, he participated to the discovery of the Rossmann Fold
in 1974. Dino returned to France in 1975 and
created a team at the Institute of Chemistry
in Strasbourg. In 1980, he founded the Crystallography and Structural Biology Department at the IBMC. In 1990, he discovered the
partition of amino-acyl-tRNA synthetases in
two classes and determined the first threedimensional structure of a class II tRNAsynthetase. Dino then worked on nuclear
receptors in collaboration with Pierre Chambon and elucidated the first crystal structure
of the retinoic acid receptor. From 2007 to
2009, he was Director of the IGBMC. n
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73
highlights
• AlExSys (Alignment Expert System) drives optimal strategies for high quality multiple alignment
and analysis of complete sequences by dissecting
the relationships between Programme strengths/
weaknesses and the information content of extensive
set of sequences.
1
probing complexity
Our research is focused on the management of the ubiquitous «data overload» from today’s high-throughput
technologies. We use complementary bottom-up and topdown approaches to study the behaviour and evolution
of biological systems, such as “hyperstructures” (macromolecular complexes, organelles, viruses…) or biological
networks (metabolic, transcriptional, interaction as well
as developmental or disease-related networks…). In the
bottom-up approach, we study basic components and integrate the data to detect relevant patterns (e.g., proteins
and their interactions within a complex). In the top-down
approach, we establish our knowledge of the system and
attempt to disassemble it, e.g. to study normal and abnormal (disease) processes. This involves the development of:
- Original algorithms and software based on an evolutionary approach to analyse hierarchical systems in the light
of their conservation and distribution in eukarya,
- New data system architectures suitable for computer and
data grids to allow rapid retrieval, organization and exploration of raw data and information and to extract hidden
knowledge,
- Bioinformatics pipelines for quality control, integration,
analysis and real time maintenance of interconnected genomics data with the goal of understanding disease origins
and identifying and developing new therapeutic targets.<
• SM2PH-db involves automatically launched and
updated cascade of data processing and analyses embedded in the BIRD system and Decrypthon data
and computer grid to allow the study and interpretation of the molecular consequences of mutations
in the context of all known human monogenetic
diseases.
shaping the future
Evolutionary systems biology
Addressing the complexity of biological systems will involve automatic value-added data processing and analysis,
requiring extensive computational power as well as rapid
access to dispersed but synchronized data resources. In
this context, our research will focus on the development
of original bioinformatics solutions deployed on advanced
computer and data technologies to ensure automated,
updated and sustained analyses.
Our approach of comparison and modeling of biological
systems will take advantage of the postulate “what is important is generally conserved”: i.e., billions of years of evolution and selection constitute a discriminating filter and a
unique source of information for interpreting what the new
data actually mean and how they can be used to address
questions that need to be answered. <
Toward integrative
bioinformatics
• The ortho-proteogenomics approach combines
original sequence analysis tools with proteomics approaches highlighting the extensive sequence error
rate in well studied proteomes and allowing the creation of Programme cascades for automatic prediction of sequence-error and proteome-level curation.
Bard N, Bolze R, Caron E, Desprez F, Heymann M, Friedrich A, Moulinierr L, Nguyen NH, Poch O Toursel T (2010)
Decrypthon Grid – Grid resources dedicated to neuromuscular disorders in “Studies in Health Technology and
Informatics», IOS Press, in press. (2010).
Olivier Poch
• Following our study of the Bardet-Biedl Syndrome and the
characterization of the BBS10 and BBS12 genes, extensive
analysis and genetic diagnosis of hundreds of families
allowed the identification of 28 novel mutations. This study
highlights the burden of private mutations in an extensively
heterogeneous disease and confirms that BBS1, BBS10 and
BBS12 are the most frequently mutated genes. n
Aniba MR, Poch O, Marchler-Bauer A, Thompson JD,
(2010) AlexSys: a knowledge-based expert system for
multiple sequence alignment construction and analysis
Nucleic Acids Res. in press. (2010).
1- Derivation of the mean square error in
the Multidimensional fitting algorithm
2- Pathways of PtdIns5P synthesis and
transformation : a)Schematic representation of phosphoinositides, fatty acids are represented only for PtdIns with co-evolving
complexes highlighted. b) Phylogenetic
distribution of proteins implicated in the
PtdIns5P metabolism in 39 eukaryotic
organisms c) Inferred PtdIns5P metabolism
in different organisms.
Friedrich A, Garnier N, Gagnière N, Nguyen H, Albou LP,
Biancalana V, Bettler E, Deléage G, Lecompte O, Muller
J, Moras D, Mandel JL, Toursel T, Moulinier L, Poch O.
SM2PH-db: an interactive system for the integrated analysis of phenotypic consequences of missense mutations
in proteins involved in human genetic diseases.
Hum Mutat. 31(2):127-35. (2010).
Muller J, Stoetzel C, Vincent MC, Leitch CC, Etal...Poch O,
Mandel JL, Dollfus H. Identification of 28 novel mutations
in the Bardet-Biedl syndrome genes: the burden of private
mutations in an extensively heterogeneous disease.
Hum Genet. 127(5):583-93. (2010).
Having been simultaneously at the Pasteur
Institute and the IGBMC, Olivier Poch obtained
a PhD from Strasbourg University on the determination of rabies virus genes sequence in
1987. He then focused on the analysis of the
viral protein sequences and predicted that all
monomeric polymerases from all living organisms may share a common unifying fold.
In 1992, he became interested in the experimental study of the yeast cell cycle while he
still worked on bioinformatics analysis, notably on tRNA synthetases where he contributed to the discovery of 2 classes in this ancestral protein family. In 1997, he joined the
IGBMC to create a Bioinformatics laboratory
and develop original approaches for multiple
sequence alignment and comparative genomics programmes. He then focused on more
integrative approaches working on functional
genomics data, ontology development, clustering algorithms and recently, turned toward
data mining and knowledge extraction approaches. n
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75
highlights
• TFIID flexibility: We have characterized major
conformational changes of the transcriptional coactivator TFIID and found that the presence of
the Taf2 subunit stabilizes an active conformation.
• Activation of transcription: The cryoEM structure of a complex containing TFIID, TFIIA and
the Rap1 activator assembled on a ribosomal gene
promoter revealed the role of TFIIA in the activation process. TFIIA is part of a molecular switch
that changes conformation upon interaction with
the activator and triggers initiation complex assembly.
1
probing complexity
Our team deciphers the three-dimensional organization of
macromolecular complexes by using high resolution cryoElectron Microscopy (EM) to visualize single molecules in
their native state and image analysis to extract signal from
noise. We study how basal transcription factors interact
with the promoter of protein-encoding genes and analyze
the transmission of activation signals mediated by cis-acting transcription factors towards the basal transcription
machinery in order to trigger increased transcription.
The study of different intermediate states reveals snapshots
of dynamic processes that highlight the conformational
changes of these nanomachines during transcription initiation. These approaches were applied to several molecular systems including the SAGA and TFIID coactivators,
but also to other systems such as TFIIH, TFIIE, RNA Polymerase I, DNA Topoisomerase II or HIV integrase, in
collaboration mainly with IGBMC team leaders.
As part of an integrated vision of cellular structural biology we analyze the organization of transcription within
the nuclei of rod photoreceptors. The biological system
used is a mouse model of a human disease: the type 7
Spinocerebellar Ataxia. Chromatin organization, histone
modification and transcriptional activity were correlated
in this context. <
shaping the future
Architecture of nucleoprotein systems
by 3-D Electron Microscopy
Future developments in the image analysis of large datasets of eukaryotic transcription complexes will reveal finer
morphological details as well as a larger number of discrete
conformational states. This wealth of information will allow
us to fit more accurately atomic structure into our cryo EM
maps and to reveal the dynamic processes underling transcription initiation.
The analysis of frozen hydrated cell sections aims at positioning the transcription process in its cellular context and
to visualize the molecular complexes in their functional
chromatin environment. More complex in vitro systems will
be established and studied to determine the structures of
integrated biological architectures taking into account transcription factors in their chromatin context.
<
Patrick Schultz
Visualizing molecules to
understand their function
• In vivo organization of transcription: The correlation of histone modifications, chromatin compaction and active RNA polymerase positions
places the transcriptional scene within the cell
nucleus. We found that transcription occurs in decondensed
chromatin at a fixed distance from the heterochromatin interface.
Papai G, Tripathi MK, Ruhlmann C, Layer JH, Weil
PA and Schultz P. TFIIA and the transactivator Rap1
cooperate to commit TFIID for transcription initiation,
Nature. 465(7300):956-60. (2010).
• Mechanism of viral DNA integration: In collaboration
with Marc Ruff we determined a 3-D model of the HIV-1
Integrase in the presence of DNA molecules. The cryoEM
structures reveal the detailed molecular architecture of the
integration complex. n
Papai G, Tripathi MK, Ruhlmann C, Werten S, Crucifix
C, Weil PA, Schultz P. Mapping the initiation binding
Taf2 subunit in the structure of hydrated yeast TFIID.
Structure. 17(3):363-373. (2009).
1- Three-dimensional model of the HIV
integrase (blue) complexed to the cellular
co-factor LEDGF (grey) in interaction with the
viral DNA (modeled in two distinct conformations in gold) and the cellular DNA (red).
2- Extended chromatin fiber (red)
visualized in an electron tomogram of a mouse
rod photoreceptor nuclei. Dense heterochromatin is depicted in green whereas the euchromatin
domain appears in blue.
Michel F, Crucifix C, Granger F, Mouscadet JF,
Korolev S, Gottik M, Nazabal A, Emiliani S, Benarous
R, Moras D, Schultz P and Ruff M. Mechanism for
viral DNA integration in the human genome by the
HIV-1 integrase and role of human LEDGF. EMBO J.
28(7):980-991. (2009).
Thauvin C, Rickling S, Schultz P, Célia H, Meunier S,
Mioskowski C (2008) Carbon nanotubes as
templates for polymerized lipid assemblies.
Nat Nanotechnol. 3(12):743-8. (2008).
Patrick Schultz graduated with a degree in Molecular Biology and Genetics from Strasbourg
University and obtained his PhD in 1987 on the
organization of chromatin working in Pierre
Oudet’s team. During his postdoc at EMBL (Heidelberg), he had the opportunity to use cryo
Electron Microscopy which opened a new prospect for visualizing molecules in their native,
hydrated, environment. When he returned to
Strasbourg he focused on the structural studies
of multiprotein complexes involved in transcription and in its regulation. In 1991 he published
the first 3-D model of a eukaryotic RNA polymerase. In 1994, the newly created IGBMC brought
him closer to X-ray crystallography and NMR
and since then he has tried to integrate these
complementary structural approaches. Following Pierre Chambon’s pioneering work on
transcription factors, he identified a structural
model for TFIIH in 2000 and worked on the comprehension of the structure and the function of
the TFIID complex. More recently, his research
has turned towards understanding chromatin
structure and the transcription units organization within the cellular environment. n
2
3
77
highlights
• We have determined the first crystal structure of eukaryotic 80S ribosome from yeast. We
have determined structures of several bacterial
70S ribosome complexes containing tRNAs and
different mRNAs. We have proposed a mechanism of mRNA movement on the ribosome during translation.
shaping the future
Ribosomes
X-ray crystallography of the yeast ribosomes will allow us
to investigate the mechanism of regulation of translation in
eukaryotes. This study will create a basis for the beginning
of x-ray study of translation system in human cells.
We will continue the investigation of the mechanism of
translocation by x-ray structure determination of different
ribosome functional complexes from bacteria and yeast.
New antibiotics developed for inhibition of the ribosome
activity in bacteria and fungi will be studied by x-ray crystallography.
<
• Our study of codon-anticodon interactions
of tRNAPhe containing hypermodified nucleoside in the anticodon loop at position 37
(ms2i6A37) have shown how natural modification is involved in preventing frame-shifting
and stabilizing mRNA-tRNA interactions.
1
probing complexity
The ribosome is a large ribo-nucleoprotein complex with
total molecular mass of 2 500 000 Dalton in bacteria and
3 300 000 Dalton in yeast. Several components contribute to the greater weight and complexity of eukaryotic
ribosomes: RNA expansion segments that are inserted into
the evolutionary conserved rRNA core and additional 25
proteins.
The ribosome performs protein synthesis using a messenger RNA template. It mediates the interactions between
mRNAs and tRNAs and it catalyses the peptide bond formation. Our group has developed methods for x-ray study
of bacterial 70S ribosome from the extreme thermophilic
microorganism Thermus thermophilus and recently for the
80S ribosome from the yeast Saccharomyces cerevisiae.
The goal of our group is to study structure and mechanism
of protein biosynthesis in bacteria, yeast and humans. <
Marat Yusupov
All about the ribosome
• High resolution structures show that tRNA
in the A and P sites communicate through
a protein rich environment suggesting a
mechanism for the control of these tRNAs
position/function by the ribosome.
• We have identified the network of ribosomal elements
involved in proofreading of tRNA by comparing three
crystal structures of the 70S ribosome with an empty A site
or the A site occupied by cognate or near-cognate tRNA. n
Jenner L, Demeshkina N, Yusupova G and Yusupov
M (2010) Structural rearrangements of the ribosome
at the tRNA proofreading step.
Nat Struct Mol Biol. in press.
Jenner L, Demeshkina N, Yusupova G, Yusupov M.
Structural aspects of messenger RNA maintenance
by the ribosome.
Nat Struct Mol Biol. 17:555-560. (2010).
1- Crystals of the ribosome from
yeast Saccharomyces cerevisiae
diffracting to 4.2A resolution.
2- 80S ribosome from yeast
Saccharomyces cerevisiae. 40S subunit
in blue, 60S subunit in yellow-green.
RNA expansion segments in red.
Yusupova G, Jenner L, Rees B, Moras D, Yusupov M
Structural basis for messenger RNA movement on
the ribosome. Nature. 444:391-394. (2006).
In 1978, Marat Yusupov began his research
at the Institute for Protein Research in Pushchino, Russia. In 1986, he obtained his PhD
on the study of ribosome structure. He then
supervised a research team at the Institute
for Protein Research and collaborated with
Dino Moras for ribosome x-ray study.
In 1996, he joined the University of California in Santa Cruz, USA and continued his
work on the ribosome. In 2001, he made a
major discovery with Harry Noller, Jamie H.
D Cate and Gulnara Yusupova and determined the complete structure of the ribosome.
This work largely contributed to the Nobel
Prize Award in 2009 to Ada E. Yonath,Thomas
A. Steitz and Venkatraman Ramakrishnan.
Since then, he dedicates himself to the study
of ribosome functioning and translation mechanisms. He became the leader of the Ribosome Team at the IGBMC in 2001. n
2
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79
From the disease to the gene and vice-versa, pathomechanims and therapeutic strategies
" We explore the genetic bases of physiological and pathological processes,
and use genetic mouse models to understand human disorders." B. Kieffer
Translational
medicine &
neurogenetics
This Programme brings together nine research
groups. Most of them address neural dysfunctions
and all of the teams share a common interest in
integrative mouse biology.
Six independent teams constitute the human genetics component founded and animated by JeanLouis Mandel (Professor of Human Genetics at
the Collège de France). This component of the
Programme is focused on deciphering the mechanisms underlying several monogenic diseases
affecting the nervous system or skeletal muscle.
Projects include the identification of genes involved and of their mutations, as well as analysis
of the normal function of cognate proteins and
pathomechanisms responsible for the clinical phenotype, as a prerequisite for the development of
novel therapeutic strategies. Among the transversal
goals shared by several teams are the development
of high-throughput sequencing approaches for
the efficient identification of mutated genes and
molecular epidemiology studies in heterogeneous
genetic diseases. Strong links have been established
with clinicians (patient recruitment, genotypephenotype studies) and with patients associations.
Many teams are involved in teaching (Medical
and Life Sciences faculties, College de France) and
bringing science closer to the lay public. Annual
meetings on important topics in Human Genetics
Mouse models of human diseases :
X-linked mental retardation, Coffin-Lowry Syndrome and
mental retardation, Bardet-Biedl syndrome, Myotonic
dystrophies, Friedreich and other recessive ataxias, Myotubularin-associated neuromuscular diseases, Polyglutamine and Huntington disease, Aneuploidies and Down
syndrome, Chronic pain, Drug abuse, Depression, Atherosclerosis and thrombosis, Metabolic syndrome.
Cellular processes involved in pathogenicity :
Cytoskeletal proteins and membrane trafficking, intracellular cell signaling and kinases, Fe-S cluster biogenesis
and cell metabolism, protein/RNA aggregation and cellular toxicity, mRNA transport, DNA repair, neurotransmission and membrane receptors, prostaglandin and leukotriene signaling
are organized at the College de France.
A novel team directed by Yann Hérault has joined
recently and addresses the genetic bases of human
chromosome 21 deficiencies with a main focus on
the Down Syndrome. The research addresses phenotype-genotype relationships and gene dosage
effects. Experimental strategies involve chromosomal engineering of the mouse genome and behavioral analysis of genetic mouse models. This team
works in close collaboration
with human geneticists.
The team headed by Brigitte
9 Groups
Kieffer explores the function
of peptidic neuromodulatory
24 Staff scientists
systems in complex behaviors.
17 Postdoctoral fellows
The principle approaches include gene targeting in mice,
30 PhD students
pharmacology and behavior,
21 Engineers/Technicians
fluorescence imaging and electrophysiology. Focus is on the
1 Assistant
opioid system and associated
signaling pathways with a major goal being to decipher the molecular bases of pain control, hedonic homeostasis and emotional behaviors. This research impacts in areas of pathological pain, drug
abuse, stress and mood disorders. This team has
strong links with both molecular biologists and
behavioral psychologists, and has recently established an international associated laboratory with
the Scripps Research Institute (La Jolla, USA).
Finally, a cardiovascular component is developing.
A team headed by Jean-Etienne Fabre investigates
signaling mechanisms leading to atherothrombosis
and has developed unique mouse models to study
the disease in vivo. A new team led by Romeo Ricci has been recruited recently. This team studies
signal transduction mechanisms underlying the
metabolic syndrome. n
81
highlights
• CUG and CCUG expanded repeats sequester the MBNL1 splicing factor. We found that
MBNL1 sequestration in DM patients leads to
alternative splicing of the BIN1 pre-mRNA. In
collaboration with Jocelyn Laporte’s team, we
found that BIN1 splicing mis-regulation results
in T-Tubules and muscle weakness in DM patients, cell and mouse models.
1
probing complexity
The RNA gain-of-function diseases are a novel class of
human genetic disorders in which expansion of repeated
nucleotides are toxic at the RNA level. These diseases
include Congenital and Adult type 1 and 2 Myotonic
Dystrophies (DM), Fragile X-Associated Tremor/Ataxia
Syndrome (FXTAS), Spinocerebellar Ataxia 10 (SCA10)
and possibly SCA12 and Huntington’s disease-like type
2. These autosomal dominant genetic diseases are caused
by expanded tri-, tetra- or penta-nucleotide repeats that
are transcribed but are not exported, and accumulate in
pathogenic nuclear RNA aggregates that sequester specific
RNA-binding proteins, leading to molecular changes ultimately resulting in the pathological symptoms.
While the general paradigm of these diseases is now established, very little is known on the detailed molecular
mechanisms involved in these disorders. Our goal is to
elucidate the molecular causes of CGG, CUG, CCUG
and AUUCU RNA toxicity in FXTAS, DM1, DM2 and
SCA10 patients, respectively. We are particularly focusing
on the RNA binding proteins sequestered by these repeats
and the cellular consequences of such sequestration.<
shaping the future
Physiopathology of the RNA gain-offunction diseases
We will pursue the identification of the RNA binding
proteins which are sequestered within the RNA aggregates
in RNA gain-of-function patients. Notably, we just found
that the FOX1 and FOX2 splicing factors co-localize with
CCUG aggregates in DM2 patients.
Furthermore, we discovered that the expression of
specific mi-RNAs is altered in skeletal muscle and heart of
Myotonic Dystrophic patients. We will study the molecular
mechanism and the consequences of these alterations.
We are currently developing in vitro and in cellulo mediumand high-throughput screens to identify pharmacological
compounds able to reverse the toxic effects of expanded
CUG, CCUG or CGG repeats. If successful, this work
would constitute a first step toward identifying compounds
able to reverse the pathogenesis in RNA gain-of-function
diseases. <
• We identified a novel function of MBNL1 as
a regulator of micro RNA processing. Consequently, the processing of the micro RNA miR1 is altered in DM patients, resulting in cardiomyocyte dysfunctions.
specific alternative splicing events regulated by SAM68 are
altered in brain samples of FXTAS patients.
• We identified that expanded CGG repeats sequester the
DROSHA/ DGCR8 complex. DROSHA is the enzyme
responsible for pre-micro-RNA processing. Consequently
in DROSHA sequestration, we observed a global alteration of the micro RNA processing resulting in neuronal
cell death in FXTAS patients. n
Dhaenens CM, Schraen-Maschke S, Tran H,
Vingtdeux V, Ghanem D, Leroy O, Delplanque J,
Vanbrussel E, Delacourte A, Vermersch P, Maurage
CA, Gruffat H, Sergeant A, Mahadevan M, Ishiura
S, Buee L, Cooper TA, Caillet-Boudin ML, Charlet-B
N, Sablonniere B, Sergeant N. Overexpression of
MBNL1 fetal isoforms and modified splicing of Tau in
the DM1 brain: two individual consequences of CUG
trinucleotide repeats.
Exp Neurol. 210(2):467-78. (2008).
Charlet-B. N., Feuerhahn S., Kong S., Ziserman H.,
Conaway J., Conaway R., Egly J.M. RNA polymerase
II bypass of oxidative DNA damage is regulated by
transcription elongation factors.
EMBO. J. 25(23):5481-91. (2006).
Nicolas Charlet-Berguerand
Fight against RNA
aggregates
• We found that expanded CGG repeats sequester the SAM68 splicing factor in FXTAS patients, cell and mouse models. Consequently,
Sellier C., Rau F., Liu Y., Tassone F., Hukema RK., Gattoni R., Schneider A., Richard S., Willemsen R., Elliott
DJ., Hagerman PJ., Charlet-B. N. Sam68 sequestration and partial loss of function are associated with
splicing alterations in FXTAS patients.
EMBO. J. January. In Press. (2010).
Human Genetics
1- Co-localization of DHPR
(green) and BIN1 (red) in mouse
isolated muscle fiber.
2- Co-localization of BIN1
(green) and RYR1 (red) in human
myotube. DNA is labeled in blue
(DAPI)
After having spent three years in Paris at
The Centre de Génétique Moléculaire (CGM)
with J. Marie’s team, followed by three
more years in T. A. Cooper’s laboratory,
Nicolas Charlet-Berguerand obtained his
PhD in Paris in 2003 on splicing, applied
to human diseases and in particular to
myotonic dystrophies. In 2003, he began
his post-graduate research on DNA repair in
Jean-Marc Egly’s laboratory at the IGBMC. In
2006, he returned to the study of myotonic
dystrophies and created a team dedicated to
this topic at the IGBMC. Today, his research
focuses also on Fragile X Tremor Ataxia
Syndrome (FXTAS) a genetic disorder that
also reveals, as in myotonic dystrophies,
toxic RNA aggregates. His team studies
these diseases and searches their associated
proteins. They also test chemical compounds
able to suppress the toxic effects and restore
normal functions in patient cells. n
2
83
highlights
• We have developed a new model for studying
in vivo atherothrombosis and have developed
new methods for investigating vasoconstriction
in mice, and for quantifying ruptures of atherosclerotic plaques.
1
probing complexity
Atherothrombosis, the occurrence of thrombosis on atherosclerotic plaques, is the main cause of myocardial infarction and stroke, the leading causes of death in developed
societies. Atherosclerotic plaques are complex lesions of
the vascular wall, provoked by oxidized lipid deposition
which initiates and maintains local inflammation. Inflammation is itself a complex process that involves numerous
lipid mediators, and its role in atherothrombosis is poorly
delineated.
To probe this complex picture, we focus our studies on the
involvement of the arachidonic pathway in atherothrombosis. These molecules have the potential to interfere with
the plaque vulnerabilization, with the vessel reactivity and
with the blood platelet behaviour. We examine in mice
how each prostaglandin and leukotriene produced by the
plaque contributes either to the plaque rupture or to local thrombosis through a direct action on platelets. In the
end, we hope to get a whole picture of the effects of these
inflammatory mediators on atherothrombosis.
Understanding the inflammation-thrombosis relationship
will improve the way atherothrombosis is prevented and
also might have important implications in other diseases
where inflammation is complicated by thrombosis, such
as cancer and auto-immune diseases. <
• We have revealed in our laboratory that murine and human plaques produce significant
amounts of PGE2 and we identified the PGE2/
EP3 pathway as aggravating atherothrombosis.
As a consequence, we demonstrated that blocking EP3 allows inhibition of atherothrombosis
without altering haemostasis, i.e. without increasing the risk of bleeding.
shaping the future
Atherosclerosis
and thrombosis
We need to keep developing our in vivo tools in order to
improve atherothrombosis detection and quantification
and are currently developing a method using MRI in
collaboration with a German team for both experimental
and clinical purposes.
Our ultimate goal is to be able to describe by which
pathways the whole inflammatory machinery impacts
atherothrombosis. When we have delineated the roles of
the main prostaglandins and leukotrienes, we will follow
three directions:
• keep investigating the arachidonic pathway through less
known molecules (lipoxins, epoxy-derived compounds)
• investigating the role of the sphingosin/ceramide axis
• examining the involvment of cytokines.
These studies should allow us to draw a global picture of
the inflammation-thrombosis link. <
Jean-Etienne Fabre
Understanding
cardiovascular diseases
• Two classical inflammatory vasoconstrictors,
LTC4 and TXA2 were used to demonstrate
that vasoconstriction can break atherosclerotic plaques, however only when they are vulnerable. We
showed that only TXA2 is produced by atherosclerotic
plaques.
Magnetic resonance molecular imaging of thrombosis in an arachidonic acid mouse model using an
activated platelet targeted probe.
Klink A, Lancelot E, Ballet S, Vucic E, Fabre JE, Gonzalez W, Medina C, Corot C, Mulder WJ, Mallat Z,
Fayad ZA. Arterioscler Thromb Vasc Biol. 30(3):40310. (2010).
• In plaques, we detected fair amounts of leukotriene B4,
a powerful chemoattractor for neutrophils. We currently
test the hypothesis that neutrophils degrade the fibrous cap
by releasing their proteases, linking infectious diseases to
the plaque rupture. We demonstrated that neutrophils can
enter the plaques and release their enzymatic content. n
Antagonists of the EP(3) Receptor for Prostaglandin
E(2) Are Novel Antiplatelet Agents That Do Not Prolong Bleeding. Singh J, Zeller W, Zhou N, Hategen
G, Mishra R, Polozov A, Yu P, Onua E, Zhang J,
Zembower D, Kiselyov A, Ramírez JL, Sigthorsson G,
Bjornsson JM, Thorsteinsdottir M, Andrésson T, Bjarnadottir M, Magnusson O, Fabre JE, Stefansson K,
Gurney ME. ACS Chem Biol. 4(2):115-126. (2009).
Vascular wall-produced prostaglandin E2 exacerbates
arterial thrombosis and atherothrombosis through
platelet EP3 receptors. Gross S, Tilly P, Hentsch D,
Vonesch JL, Fabre JE.
J Exp Med. 204(2):311-20 (2007).
1- SEM picture showing the rupture
of an aortic murine atherosclerotic
plaque. Inside the fracture, activated
platelets are mounting the thrombotic response.
After working for ten years as a Cardiologist
in an intensive care unit, Jean-Etienne Fabre
worked for the pharmaceutical industry
for three years at LAFON Laboratories. In
1995, he joined J.M. Isner’s laboratory at
Tuft University in Boston, (USA) to work
on angiogenesis. There he studied the
effects of conversion enzyme inhibitors on
angiogenesis. He then joined B.H. Koller’s
team at the University of North Carolina,
Chapel Hill USA. There he showed that
P2Y1 was an ATP receptor in blood platelets
and discovered the existence of LTB4
transcellular metabolism. Jean-Etienne also
proved that PGE2 promoted thrombosis
in vivo. He obtained his PhD in 2000 from
Strasbourg University. In 2001, he was
contacted by Pierre Chambon and joined
the IGBMC to focus on the link between
explosive thrombosis and inflammation of
atherosclerotic plaques. n
2
85
highlights
1
probing complexity
Mental retardation (MR), defined as major deficits in cognitive functions manifesting early in life, originates from
highly heterogeneous causes, that prominently include
single gene mutations. We study several of these genes
trying to decipher their function at the molecular, cellular and central nervous system level, as well as the consequence of their deficit in neurons and on cognitive functions in the mouse. We study the FMR1 gene mutated
in the Fragile X MR syndrome, the most common cause
of inherited MR, as well as two protein-kinase encoding
genes, RSK2 and PAK3, responsible for X linked forms
of syndromic (Coffin-Lowry) or non-syndromic MR. We
are also involved in genetic studies of the Bardet-Biedl
syndrome, a pleiotropic ciliopathy, and in genetic diagnosis applications related to MR. Our FMR1 studies focus
on the processes involved in mRNA transport and local
translation in dendrites that appear important for synaptic
plasticity. Another focus is the role of signal transduction
pathways that include RSK kinases and PAK kinases and
their role in regulation of neurotransmission and in synaptic plasticity. Knowledge of the precise functions of
these proteins will contribute to the better understanding
of molecular pathomechanisms leading to MR and may
open paths towards better treatments.<
• Protein networks: With B. Bardoni, we identified several protein interactors of FMRP, notably the
conserved CYFIP proteins, that interact with Rac1
GTPase and the WAVE complex, key regulators of
cytoskeletal actin remodeling.
• Metabolism of neuronal mRNAs (Dr. Hervé Moine):
We showed that FMRP binds specifically mRNAs
containing G(uanine)-quartet motif and also a triple
stem-loop motif in SOD1 mRNA. We found that
FMRP regulates its own mRNA splicing and the
formation of mRNA stress granules. We recently
showed that the G-quartet motifs present in the 3’
untranslated region of key neuronal mRNAs act as
«zipcode» for their localization to dendrites (unpublished).
• Signal transduction: Found increased level of
cortical dopamine in our Rsk2 deficient mice that
is caused by increased tyrosine hydroxylase (TH) activity. We provided evidence that loss of neurons due
Bechara EG, Didiot MC, Melko M, Davidovic L, Bensaid M, Martin P, Castets M, Pognonec P, Khandjian
EW, Moine H, Bardoni B. A novel function for fragile
X mental retardation protein in translational activation.
PLoS Biol. 7(1):e16. (2009).
shaping the future
Mechanisms of monogenic forms
of mental retardation
Gaining a thorough insight into the mechanisms
underlying MR will contribute to better understand
the processes of normal cognition, notably the molecular events and signaling pathways implicated in
activity-dependent local changes that take place in
neuronal processes. Our major goals are to :
● define and understand the molecular signals that
are involved in controlling mRNA transport and local
protein synthesis in neurons, and how they impact
fragile X pathomechanisms.
● understand the mechanisms leading to increased
apoptosis and to AMPA receptor dysfunction in
Rsk2-KO mice and define the contribution of each
of these deregulations to the cognitive dysfunction.
● define the functional interactions between PAK3,
Rsk2 and FMRP.
In collaboration with the teams of M. Koenig and
J. Laporte, and with the DNA diagnostic lab (Strasbourg Hospital), we will develop high-throughput
sequencing strategies for gene identification and
molecular diagnosis in MR. <
to impaired apoptosis and a defect in AMPA neurotransmission and plasticity might contribute to cognitive dysfunction
in Rsk2 KO mice.
• Gene discovery: Contributed to the identification of two
major genes mutated in Bardet-Biedl syndrome that defined
a novel chaperonin family (collaboration with the team of
Pr. H. Dollfus), and to the definition of a new microdeletion syndrome (del16p11.2) associated to developmental delay and obesity (with the DNA diagnostic lab at Strasbourg
Hospital, and a large international collaboration). n
Didiot MC, Subramanian M, Flatter E, Mandel JL,
Moine H. Cells lacking the fragile X mental retardation
protein (FMRP) have normal RISC activity but exhibit
altered stress granule assembly.
Mol Biol Cell. 20:428-37. (2009).
1- The G(uanine) quartet structure is a binding
site for the Fragile X Mental Retardation Protein
on neuronal mRNAs (left and middle). Presence
of a G-quartet-FMRP binding site in the
3’-untranslated region of a mRNA enables its
dendritic localization in cortical neurons (green
signal on right panel).
2- Dendritic spines of hippocampal neurons
revealed by actin (red) and Neurabin2 (green)
staining. DAPI staining of the nuclei (blue).
Didiot MC, Tian Z, Schaeffer C, Subramanian M,
Mandel JL, Moine H. The G-quartet containing FMRP
binding site in FMR1 mRNA is a potent exonic splicing
enhancer. Nucleic Acids Res. 36:4902-12. (2008)
Marques Pereira P, Gruss M, Braun K, Foos N, Pannetier S, Hanauer A. Dopaminergic system dysregulation
in the mrsk2 KO mouse, an animal model of the
Coffin-Lowry syndrome.
J Neurochem. 107:1325-34. (2008).
Human Genetics
Jean-Louis Mandel
André Hanauer
Understanding the X-linked
mental retardations
Jean-Louis Mandel earned an MD and MSc
and taught genetics at the Strasbourg University before being nominated Professor at
the Collège de France in 2003. His research in
human genetics has brought major contributions, notably to our understanding of neuromuscular genetic diseases. In 1991, his team
notably identified unstable mutations involving nucleotide triplet repeat expansions responsible for the Fragile X syndrome. From
2002 to 2009, he directed the IGBMC jointly
with Dino Moras. Today, he leads the Genetic
Diagnosis Laboratory of the Strasbourg Hospital and is in charge of a team with André
Hanauer on X-linked mental retardation.
André Hanauer obtained his PhD in 1989 and
is Associate Professor at the University of
Strasbourg. In 1996, he identified the gene
responsible for Coffin-Lowry’s syndrome.
The team he conducts jointly with Jean-Louis
Mandel has made major contributions to the
understanding of functional and genetic aspects of the Rsk2 gene that is responsible for
Coffin-Lowry syndrome. n
2
87
highlights
• The Aneuploid zoo: a comprehensive series of
mouse model for Aneuploidies linked to human chromosome 21: Homologous and syntenic regions of
the Human chromosome 21 (Hsa21) are found
on murine chromosomes 16, 17 and 10. We used
chromosomal engineering, a strategy we pioneered
a few years ago, in order to develop a comprehensive series of new mouse models carrying segmental aneuploidies for all the regions that are homologous to Hsa21 in the mouse.
1
probing complexity
Our goal is to identify dosage sensitive genes and we focus
our interests on a few aneuploid syndromes: the Down
syndrome (DS), a frequent aneuploidy affecting 1 newborn out of 700, identified as the consequence of Trisomy
21 and the rarer Monosomy 21 (M21), caused by the loss
of one copy of chromosome 21 (Hsa21).
Despite prenatal diagnosis, the incidence of DS is still high
partly due to the increase in the maternal age and to the
social disparity in the prenatal follow-up. DS is associated with mental retardation, heart defect and a large panel
of dysmorphologies affecting the face and the skeleton
Changes in metabolism and increased frequencies of some
pathologies such as leukemia, autism, epilepsy and early
onset Alzheimer disease are also observed.
A few individuals with DS alterations carry a segmental
duplication instead of a complete trisomy. The fifty cases
described in the literature are very informative but still not
enough to understand further the phenotype-genotype relationship. Thus we decided to use the mouse as a model
system in order to identify dosage sensitive genes (or other
genetic units) that could have a direct or indirect effect on
the DS phenotype. <
shaping the future
Physiopathology of aneuploidy, gene dosage
effect and Down syndrome
We plan to focus on three objectives: (1) To address the
phenotype–genotype relationship integrating human data;
(2) To identify candidate genes and pathways involving
dosage sensitive genes responsible for DS and M21
syndromes and (3) To validate new therapeutic approaches
in preclinical models with the aim of facilitating the life of
people with DS. Furthermore, this study will challenge the
balance hypothesis underlying dosage sensitivity suggesting
that the stoichiometry of the subunits participating in multiprotein complexes have to be maintained to perform their
biological function. In addition the contribution of the noncoding sequences and of the chromosomal organization
of the aneuploid phenotypes will be carefully evaluated.
Besides this main project, we are working with human
geneticists to study new aneuploid syndromes in the mouse
to develop new strategies to evaluate the contribution of
copy number variation to human disease and physiology. <
• Tackling the genotype-phenotype relationship in
DS models: With this aneuploid zoo for Hsa21 we
are performing a comprehensive phenotypic analysis for behavior, cognition, morphology and physiology in parallel with gene expression profiling.
This strategy led us to identify the consequence
of Monosomy 21 on the inflammatory and lung
functions and the contribution of some telomeric
part of Hsa21 to the DS behavioral impairments.
Lopes Pereira, P., Magnol, L., Sahún Abizanda, I.,
Brault, V., Duchon, A., Prandini, P., Gruart, A.,, Bizot,
J-C, Chadefaux-Vekemans, B., Deutsch, S., Trovero, F.,
María Delgado-García, J., Antonarakis, S.E., Dierssen,
M. and Herault Y. A new mouse model for the trisomy
of the Abcg1-U2af1 region revals the complexity of
the combinatorial genetic coded of Down syndrome
Hum. Mol. Genet. 18:4756-4769. (2009).
Yann Hérault
Mice models to study gene
dosage effects
• Contribution of regions and candidate genes to aneuploid disorders: These studies identified several genetic loci
contributing to DS phenotypes, acting either positively or
negatively on specific functions. This hypothesis allows us
to explain part of the phenotypic variability observed in
DS patients. Our current analysis of the contribution of
additional regions will help to understand further the physiopathology of the DS. n
1- Pyramidal neurons from the
hippocampus.
2- Tackling the hippocampal changes
in DS models involved in learning
and memory.
Dierssen, M., Herault, Y., Estivill, X. Aneuploidy: from
a Physiological Mechanism of Variance to Down Syndrome. Physiol. Rev. 89:887-920. (2009).
Duchon, A., Besson, V., Lopes Pereira, P., Magnol,
L., and Hérault, Y. Inducing segmental aneuploid mosaicism in the mouse through Targeted Asymmetric
Sister Chromatid Event of Recombination (TASCER).
Genetics. 180:51-59. (2008).
Yann Hérault graduated from the Ecole Normale Supérieure and obtained his PhD on
the transcription regulation of clusterin at
the ENS in Lyon in 1993. He then became
interested in developmental biology and
joined Duboule’s laboratory at the University of Geneva in order to study Hox genes
regulation. In 1998, he created the TAMERE
method, an in vivo chromosome engineering tool. While working on functional redundancy, he became interested in Down’s
syndrome, a disease also due to gene dose
effects. He created a resource of trisomic
mice models for almost the entire Down’s
syndrome homolog genes in mouse. From
2000 to 2009, he participated and led the
Transgenesis and Archiving of Animal Models unit in Orléans. He joined the IGBMC in
2010 as the director of the Mouse Clinic Institute and leads a team aiming at mapping
genotypes / phenotype relations in Down’s
syndrome. n
2
89
highlights
1
probing complexity
Opiates have been used for thousands of years for their
pain-relieving and rewarding properties. Opiates produce
their potent effects by activating opioid receptors in the
brain, thereby highjacking a complex neuromodulatory
system. Opioid receptors (mu, delta, kappa and nociceptine/orphanineFQ) are normally stimulated by endogenous peptides to control pain and stress responses, as well
as emotional and addictive behaviors.
Our goal is to tackle the role of opioid and related neuropeptide systems in brain physiology, as well as neurological and psychiatric disorders. We address molecular
mechanisms underlying the development of chronic pain
and associated affective disorders and investigate molecular adaptations that develop under repeated exposure to
drugs of abuse, and contribute to craving and relapse. We
explore potential roles of these receptors in other areas of
psychiatric disorders, and identify neurons where the receptors operate to control behavioral responses. Finally,
we use genome-wide approaches to discover novel molecular targets for drug abuse research.
Our laboratory uses gene targeting approaches in mice
(knockout, conditional knockout and knock-in), behavioral analysis, pharmacology, as well as receptor and cellular
imaging to achieve these goals. <
• We have demonstrated that a single receptor
protein, the mu opioid receptor, mediates both
therapeutic and adverse effects of clinically useful opiates. This receptor also mediates rewarding properties of other drugs of abuse, and
natural rewards.
• We have discovered an unexpected role of
delta opioid receptors in anxiety and depression,
which has important clinical implications. We
have uncovered unanticipated and opposing
contributions of mu and delta receptors in selfcontrol, opening novel avenues towards understanding behavioral inhibition.
• We have identified novel genes, whose role in
addictive behaviors is yet unknown.
• We have created knock-in mice where delta
opioid receptors are directly visible in vivo. This
Olmstead C., Ouaggazzal A-M. and Kieffer B. L. Mu and
delta opioid receptors oppositely regulate motor impulsivity
in the signaled nose poke task Cited in the Editor’s choice
section of Science PLoS ONE 4(2):984-985. (2009).
shaping the future
Opioid systems and
brain function
Our goals are to :
● futher develop site-specific gene knock-out in targeted
neurons to identify receptor populations governing addictive
behaviors and pain relief.
● continue to study delta and nociceptin orphanin peptide
receptors
(NOP) as potential therapeutic targets in
inflammatory pain, mood disorders, and cognitive deficits.
● explore the role of novel genes in cognitive, emotional and
addictive behaviors.
● continue to investigate the abstinent brain at behavioral,
genetic and imaging levels.
● develop novel mutant mice with fluorescent receptors
together with dynamic neural imaging approaches, to
elucidate molecular bases of receptor adaptations and
receptor-receptor interactions in vivo. <
Brigitte Kieffer
Specialist in opioid receptors
unique tool has allowed us to describe receptor anatomy
throughout the nervous system at cellular and subcellular
levels, and to investigate real-time receptor trafficking in
live neurons and to understand behavioral desensitization
mechanisms. This is a ground-breaking approach in the
field of G protein-coupled receptor biology and drug discovery. n
Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F,
O’Donnell D, Kieffer BL and Basbaum AI. Dissociation of the
opioid receptor mechanisms that control mechanical and
thermal pain. Cell 137:1148-59. (2009).
1- Fluorescently-labelled opioid
receptors visible in the brain
hippocampus of genetically
engineered mice.
2- Direct opioid receptor
visualization in live neurons
Pradhan A., Becker J., Scherrer G., Tryoen-Toth P., Filliol D.,
Matifas A., Massotte D., Gavériaux-Ruff, C and Kieffer B. L.
In vivo delta opioid receptor internalization controls behavioral responses to agonists. PLoS ONE 4(5):e5425. (2009)
Scherrer G., Tryoen-Tóth P., Filliol D., Matifas A., Laustriat D.,
Cao Y. Q., Basbaum A. I., Dierich D., Vonesh J.-L., GavériauxRuff C. and Kieffer B. L. Knock-in mice expressing fluorescent delta opioid receptors uncover G protein coupled
receptor dynamics in vivo
Proc. Natl. Acad. Sci. USA. 103:9691-6. (2006)
As Assistant Professor at the University of
Strasbourg, Brigitte Kieffer isolated, in 1992,
the first gene encoding an opioid receptor
paving the way towards understanding genetic bases of opioid-controlled behaviors.
Using gene targeting in mice she demonstrated that a single receptor protein, the
mu opioid receptor, mediates both potent
analgesic and addictive effects of morphine.
She also discovered anxiolytic and antidepressant activities of the delta opioid receptor.
Her work has important implications in basic
neurosciences and the biomedical community. From 1994 to 2006 she was a Professor
at the Faculty of Pharmacy in Strasbourg
and is currently a Research Director at Inserm. She has also been a visiting Professor
at University of California, Los Angeles since
1998. She joined the IGBMC with her team in
2001. In 2004, she received the Loundsberry
Award from joined French and US Academies of Science and became a EMBO Member in 2009. n
2
91
highlights
• Identification of the genes defective in Friedreich ataxia and ataxia due to Coenzyme Q10
deficiency, both coding for novel mitochondrial
proteins (frataxin and ADCK3) supporting assembly of components of the respiratory chain.
Construction and characterization of the first
murine and cellular models of Friedreich ataxia
for preclinical drug screenings.
1
probing complexity
Recessive progressive ataxias represent a heterogeneous
group of neurological disorders characterized by the degeneration of the cerebellum and/or the spinocerebellar and
posterior columns of the spinal cord.
Albeit ataxia is the prominent symptom, recessive progressive ataxias often combine additional features such as
peripheral neuropathy, pyramidal and/or extrapyramidal
signs, nystagmus, oculomotor apraxia, ophthalmoplegia,
optic atrophy, deafness, mental retardation, and epilepsy,
as well as non-neurological features. Due to these associated signs and symptoms, differential diagnosis is often
difficult with related disorders such as spastic paraplegias
with cerebellar involvement, sensory ataxic neuropathies,
congenital ataxias, metabolic ataxias, periodic ataxias,
cerebellar hypoplasias, and the CACH and Joubert syndromes. We have opted to tackle the very high clinical and
genetic heterogeneity of the recessive ataxias by linkage
studies of large consanguineous families referred to us by
collaborating neurologists worldwide. Today, at least 15
genes of recessive progressive ataxias have been identified,
of which seven were identified by or in collaboration with
our group. Mutations of these genes account for about 50
to 60% of the cases, indicating that many rare forms of
recessive ataxias remain to be identified. <
shaping the future
Recessive ataxias
The publication of the first and subsequent drafts of the
human genome sequence has allowed the identification
of an increasing number of genes and mutations
causing mendelian disorders. It has also revealed part
of the incredible complexity of these disorders, due to
underestimated genetic and phenotypic heterogeneity.
A future impact of the human genome project will be the
availability of personalized human genome sequencing (2nd
and 3rd generation high-throughput sequencing methods).
In addition to raising great concerns about ethical issues,
this possibility paves the way to molecular diagnosis for
clinical practice of (almost) any mendelian disorder. Our
aim is to develop applications of the next generation highthroughput sequencing for diagnostic purposes and further
unravel the complexity of the disorders for which DNA
samples of patients are referred to us.<
• Identification of novel forms of inherited
ataxias that associate cerebellar degeneration,
sensorimotor peripheral neuropathy and oculomotor apraxia. Identification of the corresponding genes, coding for novel nuclear proteins,
aprataxin and senataxin, involved in DNA repair
and RNA maturation.
Michel Koenig
A crossed career between
medicine and genetics for
rare diseases diagnosis
• Identification of the genes defective in Giant
Axonal Neuropathy, Ataxia with isolated Vitamin E Deficiency, Marinesco-Sjögren Syndrome
and Salih Ataxia, coding for cytosolic proteins involved in
various functions of membranes and cytoskeleton.
M. Assoum, M.A. Salih, N. Drouot, D. H’Mida-Ben
Brahim, C. Lagier-Tourenne, A. AlDrees, S.A. Elmalik,
T.S. Ahmed, M.Z. Seidahmed, M.M. Kabiraj, M. Koenig
Rundataxin, a novel protein with RUN and diacylglycerol
binding domains, is mutant in a new recessive ataxia.
Brain. (In press) (2010).
• We identified all disease genes by the pioneering use of
homozygosity mapping and high density genetic marker
analysis. Their identification had immediate and important applications for diagnosis of recessive ataxias in clinical practice. n
M. Anheim, B. Monga, M. Fleury, P. Charles, C. Barbot, M.
Salih, J.-P. Delaunoy, M. Fritsch, L. Arning, M. Synofzik, L.
Schöls, J. Sequeiros, C. Goizet, C. Marelli, I. Le Ber, J. Koht,
J. Gazulla, J. De Bleecker, M. Mukhtar, N. Drouot, L. Ali-Pacha, T. Benhassine, M. Chbicheb, A. M’Zahem, A. Hamri, B.
Chabrol, J. Pouget, R. Murphy, M. Watanabe, P. Coutinho,
M. Tazir, A. Durr, A. Brice, C. Tranchant and M. Koenig.
Ataxia with oculomotor apraxia type 2: clinical, biological
and genotype/phenotype correlation study of a cohort of 90
patients. Brain. 132: 2688-2698. (2009).
C Lagier-Tourenne, M Tazir, LC López, CM Quinzii, M
Assoum, N Drouot, C Busso, S Makri, L Ali-Pacha, T Benhassine, M Anheim, D Lynch, C Thibault, F Plewniak, L
Bianchetti, C Tranchant, O Poch, S DiMauro, JL Mandel,
MH Barros, M Hirano, M Koenig. ADCK3, an ancestral
kinase, is mutated in a form of recessive ataxia associated with Coenzyme Q10 deficiency.
Am J Hum Genet. 82:661-672. (2008).
Human Genetics
1- Expression of gene identified in
Cos cells (electronic microscopy)
2- Gene Identification, linkage,
sequencing & light Scanner
Michel Koenig trained in medicine and biology. In 1986, he obtained a PhD in genetics
on the human X and Y chromosomes cartography. He went on to pursue his post-doc
with Louis Kunkel’s team at the Harvard Medical School, USA until 1989. At that time,
this team had just discovered the Duchenne
muscular dystrophy gene and Michel Koenig
contributed to its characterization. In 1990 he
obtained his MD and integrated Jean-Louis
Mandel’s team to work on recessive ataxias.
The gene responsible for Friedreich’s ataxia
was identified in 1996 and enabled the development of mouse models. As a result, many
other recessive ataxia genes were identified.
Since 1996, he works with the Strasbourg
Hospital and his discoveries are now used
by neurologists for rare genetic disorder diagnoses. Michel has led his own team at the
IGBMC on recessive ataxias since 2002. n
2
93
highlights
• We identified and characterized the myotubularins family, phosphoinositides phosphatases
mutated in several neuromuscular diseases and
implicated in endocytosis and autophagy.
• We identified the first mutations in amphiphysin 2 (BIN1), previously described as a tumor
suppressor, in autosomal centronuclear myopathy. Mutations either impact on its membrane
remodelling property or disrupt its binding with
dynamin 2, another protein mutated in such diseases.
1
probing complexity
We study rare and severe neuromuscular disorders caused
by mutations in proteins affecting organelles and membrane trafficking. Our principle focus is on three families
of proteins that regulate or are regulated by membrane
lipids: the phosphoinositide phosphatase myotubularins,
the membrane remodelling amphiphysins and the membrane fissioning GTPase dynamins. Both myotubularins
and dynamin 2 are mutated in centronuclear myopathies,
severe congenital myopathies characterized by mislocalisation of nuclei and in Charcot-Marie-Tooth peripheral
neuropathies, suggesting a common mechanism.
While focusing on these genetic diseases, our approaches
are multidisciplinary and encompass the identification of
the implicated genes by high-throughput sequencing, the
study of the molecular and cellular functions of these proteins in cells and in C. elegans, the validation of mammalian disease models, and the use of viral vectors (AAVs) for
pathophysiology studies and preclinical therapeutic trials.
In parallel, we study the function of these proteins in skeletal muscle under normal and pathological conditions
through the development of novel imaging methods (correlative microscopy and in vivo imaging) in close contact
with the IGBMC platforms. <
shaping the future
Mechanisms of
neuromuscular diseases
In order to better understand the molecular basis of
severe neuromuscular diseases and to propose possible
therapeutic targets and approaches, we aim at:
● identifying additional genes implicated in neuromuscular
diseases through the development of high-throughput
sequencing strategies. Such approaches are at the heart of
the future personal medicine based on the knowledge of
our own genome.
● characterizing the link between membrane remodeling
and organelle positioning and the implication of the
cytoskeleton. This work should point to novel pathways
implicated in the late maturation and structural maintenance
of skeletal muscle fibers.
● using viral transfer in mouse to generate and rescue
muscle weakness.
● validating confocal macroscopy for non-invasive
monitoring of muscle in mammals. <
• Together with the IGBMC imaging platform, we validated integrated methods for high pressure freezing and
correlative light-electron microscopy, linking dynamic live
cell imaging to 3D ultrastructure.
• We developed and transferred most of the existing molecular diagnostic strategies for the different forms of centronuclear myopathies to the Genetic Diagnosis lab at Strasbourg Hospital. n
Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C, Sanoudou D, Beggs AH, Allard B, Mandel JL, Laporte J, Jacquemond V, Buj-Bello A. Defective
excitation-contraction coupling in muscle fibres lacking
myotubularin phosphoinositide phosphatase. Proc Natl
Acad Sci U S A. 106 (44):18763-18768. (2009).
Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren-Pettersson C, Iwarsson I, Kingston H, Garnier JM, Biancalana V, Oldfors A, Mandel JL, Laporte J. Mutations in
amphiphysin 2 (BIN1) disrupt interaction with dynamin
2 and cause autosomal recessive centronuclear myopathy. Nature Genetics. 39:1134-1139. (2007).
Jocelyn Laporte
Interdisciplinarity for the
study on neuromuscular
diseases
• Using a mouse model for X-linked centronuclear myopathy, our group showed that the
muscle weakness is linked to T-tubules and calcium homeostasis defects.
Spiegelhalter C, Tosch V, Hentsch D, Koch M, Kessler
M, Schwab Y, Laporte J. From dynamic live cell imaging
to 3D ultrastructure: integrated methods for high pressure freezing and correlative light-electron microscopy.
PLoS ONE 5(2):e94. (2010).
Human Genetics
2
1- Co-localisation between the early
endosome antigen 1 protein (green)
and the Phosphoinositide 3-monophosphate detected with a biosensor
(red). DNA in blue.
2- Homozygous mutation of the
BIN1 gene in a consanguineous
family. Above : chromatopherogram,
below : pedigree of the affected
family.
After completing studies in technical
formation at the Strasbourg School of
Biotechnology (ESBS), Jocelyn Laporte did
his PhD with Jean-louis Mandel and identified
in 1996 the myotubularin gene (MTM1)
involved in centronuclear myopathies. He
became a team leader at the IGBMC in
2007. The same year, his team brought to
light the involvement of amphiphysin 2 in
myopathies. His team’s research is based
on a interdisciplinary approach from human
genetics to therapeutic approaches through
protein functional analysis and animal
models development.
Currently his team participates in the
validation of new sequencing and imaging
technologies. The team’s research is both
fundamental and applied and they work
closely with the laboratory for genetic
disease diagnosis at the Strasbourg
Hospital. n
95
highlights
• Through conditional knockout approaches,
we have developed the first mouse models for
FRDA, which reproduce important progressive
features of the human disease. With these models, we have shown that the primary event in
the disease is the deficiency in mitochondrial
Fe-S proteins followed by a secondary mitochondrial iron accumulation. More recently, we
have provided the first direct evidence that frataxin is necessary for the proper assembly of extra-mitochondrial Fe-S proteins in mammalian
tissues, both cytosolic and nuclear.
1
probing complexity
The laboratory is dedicated to unraveling the causes and
mechanisms of progressive recessive ataxias, which are
neurodegenerative disorders that affect the cerebellum
and/or the spinal cord. Recessive ataxias represent a heterogeneous set of severely disabling neurological disorders estimated to affect 1/20,000 individuals in Europe.
Friedreich ataxia (FRDA), the most common recessive
ataxia, is characterized by progressive gait and limb ataxia
associated with hypertrophic cardiomyopathy and an increased incidence in diabetes. The disease is due to severely
reduced levels of frataxin, a highly conserved mitochondrial protein thought to be involved in multiple iron-dependent mitochondrial pathways. In particular, frataxin is
proposed to be involved in iron-sulfur (Fe-S) cluster biosynthesis. Fe-S clusters are critical redox active prosthetic
groups that are present in proteins involved in numerous
essential cellular processes ranging from nuclear genome
stability, protein translation to mitochondrial metabolism.
Mitochondria contain a complex system for assembly of
Fe/S metal centers and their insertion into proteins. In addition to unravelling the pathophysiology of the disease,
we aim to understand the molecular mechanism of mammalian Fe-S cluster biogenesis, with a particular interest
in the role of frataxin. Our strategy combines human genetics, biochemistry, cell biology and animal models. <
shaping the future
Biology and physiology
of recessive ataxia
The objectives of the laboratory are to further elucidate the
molecular mechanism underlying neuronal dysfunction in
FRDA and XLSA/A, two recessive ataxia linked to Fe-S cluster
deficit and ARCA2, a newly discovered recessive ataxia
linked to Coenzyme Q10 deficit. We will develop animal
models for ARCA2 and XLSA/A, as well as neuronal cellular
models for the three diseases. In particular, the recent
technical advances in the generation of induced pluripotent
stem cells (iPS) from somatic cells provide a powerful tool
to create disease-specific cellular models. Furthermore, to
uncover common pathways among recessive ataxia leading
to neuronal dysfunction, comparative transcriptomic and
proteomic analysis will be performed. In parallel, we will
continue functional studies to further unravel the molecular
steps of Fe-S biogenesis and coenzyme Q10 biogenesis, two
fundamental pathways in the mitochondria. <
• We have developed different cell models based either
on antisense strategy reproducing the quantitative defect
found in patients or on expression of frataxin carrying disease-causing mutation. These models exhibit proliferation
defects associated with specific biochemical features of the
disease and are therefore good models for drug screening.
• We have shown that idebenone, a CoQ10 analog in clinical use, has a significant effect on the cardiac function
and the life span of the murine cardiac model. n
Calmels N., Schmucker S., Wattenhofer-Donzé M.,
Martelli A., Vaucamps N., Reutenauer L., Messaddeq
M., Bouton C., Koenig M., Puccio H. The first cellular
models based on frataxin missense mutations that
reproduce spontaneously the defects associated
with Friedreich ataxia. PlosOne. 4(7):e6379. (2009)
1- Mitochondrial dysregulation and
iron accumulation in cardiac tissue
from mouse model of Friedreich
ataxia.
2- Human neurons (red: bIII-tubulin) and astrocytes (green: GFAP) differentiated from induced pluripotent
stem cells (iPS) derived from adult
fibroblasts.
Schmucker S, Argentini M., Carelle-Calmels N., Martelli A, Puccio H. The in vivo mitochondrial two-step
maturation of human frataxin.
Human Molecular Genetics. 17(22):3521-31. (2008).
Martelli A., Wattenhofer-Donzé M., Schmucker S.,
Bouvet S., Reutenauer L., and Puccio H. Frataxin is
essential for extramitochondrial Fe-S cluster proteins
in mammalian tissues.
Human Molecular Genetics. 16(22):2651-8. (2007).
Hélène Puccio
Understanding the
molecular mechanisms of
recessive ataxia
• By combining in vitro and in vivo approaches,
we have recently demonstrated that frataxin
interacts with the preassembled core complex
involved in the early steps of de novo Fe-S biogenesis, providing a new understanding of the
sequential steps of Fe-S biosynthesis in vivo.
Schmucker S and Puccio H. Understanding the
molecular mechanisms of Friedreich’s ataxia to
develop therapeutic approaches. Human Molecular
Genetics. 19(R1):R103-10. (2010).
Human Genetics
After obtaining her PhD in Genetics from
Harvard University, USA in 1998, Hélène
Puccio joined the group of Michel Koenig
at the IGBMC to work on the molecular
pathogenesis of Friedreich ataxia (FRDA).
In 2001, she was appointed Inserm research
associate and has since been the principal
investigator on the FRDA project. Her
research focuses on understanding the
physiopathology of FRDA through the
development of animal and cellular models
and on the development of therapeutic
approaches.
She was awarded the Pediatric Pathology
Prize in 2005 and also received the label
"Equipe FRM". In 2007, she obtained the
prestigious Young Investigator ERC award,
and in 2008 she received the Dr. Jean Toy
Prize from the Academy of Sciences and was
promoted Inserm Research Director. n
2
97
highlights
• Polyglutamine expansion and short polyglutamine tract have similar structural properties
in vitro. This contradicts the hypothesis that
polyglutamine can adopt a toxic structure only
beyond a specific length and rather suggests that
toxicity increases with polyglutamine length and
manifests when cellular mechanisms against
toxicity are overwhelmed.
1
probing complexity
Polyglutamine diseases are ten adult-onset genetic disorders that result in the degeneration of selected brain areas.
They are caused by an expansion of unstable CAG trinucleotide repeats coding for toxic polyglutamine (polyQ)
expansions in ubiquitously expressed disease proteins. Understanding the molecular and cellular mechanisms underlying polyQ toxicity and neurodegeneration is essential
to develop effective treatments against these incurable diseases. To this end, our strategy combines biochemistry,
biophysics, cell biology and analysis of mouse models
of two polyQ disorders: Huntington’s disease (HD) and
Spinocerebellar ataxia type 7 (SCA7). Our plans are : 1)
to study the interaction and aggregation properties of
proteins harboring polyQ expansion to understand why
they become neurotoxic ; 2) to study signaling pathways
and gene expression to understand how affected neurons
respond to toxic stress and how they degenerate; 3) to investigate the mechanism of instability of CAG repeats in
HD, which generates larger expansions associated with
increased protein toxicity and is particularly important in
the striatum, the primary target in HD. Our ultimate goal
is to identify effective treatments for polyQ disorders. <
• Our SCA7 transgenic mouse recapitulates
the retinal degeneration affecting the patients.
Expression profile analysis of SCA7 mouse retina reveals that transcriptional alterations compromise the photoreceptor differentiation status
and function.
shaping the future
Pathogenic mechanisms
of polyglutamine expansion diseases
We aim to understand the relationship between the
polyQ structure, aggregration and toxicity and are using
aggregation modulators as tools to delineate the aggregation
mechanisms and combine theses with biological, structural
and computational approaches.
In the SCA7 mouse PolyQ toxicity induces not only
photoreceptor death involving apoptotic and non-apoptotic
mechanisms but also proliferation, which may partially
compensate for photoreceptor loss. We are studying
the molecular mechanisms underlying these exceptional
degenerative and potentially regenerative processes in this
model.
To further understand the mechanisms underlying CAG
instability in HD, we combine in vitro and in vivo approaches
and investigate the role of Parp1, which coordinates BER
(Base Excision Repair) by facilitating the remodeling of
chromatin and the recruitement of BER factors to DNA
lesions. <
Yvon Trottier
Understanding the
Huntington disease
• Polyglutamine aggregation triggers a cellular
stress response involving the activation of AP1
transcriptional pathway in the SCA7 mouse
retina. AP1 activation correlates with repression of genes
involved in photoreceptor function. Inhibiting AP1 in the
SCA7 mouse delays the retinal phenotype.
• Stoichiometry of the DNA repair proteins DNA Polymerase ß and Flap endonuclease 1, which are involved
in Base Excision Repair (BER), contributes to the tissue
selectivity of CAG instability in HD mice. n
Yefimova MG, Messaddeq N, Karam A, Jacquard C,
Weber C, Jonet L, Wolfrum U, Jeanny JC, Trottier
Y. Polyglutamine toxicity induces rod photoreceptor
division, morphological transformation and death in
Spinocerebellar ataxia 7 mouse retina.
Neurobiol Dis. (in press) (2010).
1- SCA7 retinal section showing
aggregates (green) of polyglutamineexpanded ataxin-7 in photoreceptor
nuclei (red, left).
2- Electron micrograph showing
structured amyloid-like fibers formed
by polyglutamines in vitro.
Goula AV, Berquist BR, Wilson DM 3rd, Wheeler VC,
Trottier Y, Merienne K. Stoichiometry of base excision
repair proteins correlates with increased somatic
CAG instability in striatum over cerebellum In Huntington’s disease transgenic mice.
PLoS Genet. 5(12):e1000749. (2009).
Klein F, Pastore A, Masino L, Zeder-Lutz G, Nierengarten H, Oulad-Abdelghani M, Altschuh D, Mandel
JL, Trottier Y. Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties:
towards a length dependent toxicity gradient.
J. Mol. Biol. 371:235-244. (2007).
Human Genetics
Originally from Canada, Yvon Trottier
obtained his PhD in 1992 at Laval University
in Québec. In 1992 he joined the laboratory
of Jean-Louis Mandel, who had just
uncovered the disease-causing triplet
repeat expansions, to work as a postdoc on Huntington’s Disease. In 1995, he
characterized an antibody able to detect
polyglutamine expansions and used it as
a tool to identify two more polyglutamine
disorders. In 2002, he studied the
proteolysis mechanism of the Huntington’s
disease protein.
His recent work on
Spinocerebellar ataxia type 7 enabled him
to show that in response to polyglutamine
toxicity, neurons undergo different cell fates
including dedifferentiation, proliferation and
death. Since 2007, he has led his own team
at IGBMC on pathogenic mechanisms of
polyglutamine expansion diseases. n
2
99
MOUSE CLINICAL INSTITUTE
¨ The mouse model has become the premier model to better understand the
fundamental mechanisms responsible for complex biological phenomena.¨
Y. Hérault
Institut CLINIQUE
DE LA SOURIS
The Institut Clinique de la Souris (ICS) is a research infrastructure of excellence for translational research and
functional genomics. Founded in 2002 by Pierre Chambon and operated by Inserm, CNRS, and the Univeristy
of Strasbourg, it provides a comprehensive set of specialized services to academic and industrial users and is a
major player in the European post-genomic era programs.
The close interaction with the IGBMC strongly contributes to the development and design of new techniques
and functional assays.
The ICS combines the capacity of generating mutant mice
on a large scale with a high-throughput and comprehensive phenotypic analysis of the animals. The Institute’s
phenotyping platforms are adapted for the study of genetically engineered mouse models and genetic reference
populations but can also be used for preclinical studies
including the validation of therapeutic targets as well as
pharmacological and toxicological studies in the mouse.
The three highly interactive departments Genetic Engineering and Model Validation, Phenotyping and Mouse Facility
generate approximately 200 genetically modified mice per
year. Phenotypic analysis cover hematology, immunology,
inflammation, blood chemistry, metabolism, cardiovascular, respiratory, sensory organs, cognition, learning, beha-
vior, reproduction, morphology etc..
The ICS plays a central role in large-scale infrastructures,
both on a national level with CELPHEDIA and on a
European level through the European Infrastructure
Programme INFRAFRONTIER. Likewise, the ICS is
a major player in various European funded programs
oriented towards mouse genetics
such as EUComm, EUmodic,
EMMA. In joining the InternaIBiSA
tional Mouse Phenotyping ConsorISO 9001/2008 in progress
tium, the ICS contributes to de6 years of partnership with
cipher mammalian gene functions
pharmaceutical companies
in order to better understand huMore than 250 mutagenesis
man physiology and disease.
or phenotyping projects
The services of the ICS will ultiper year
mately help the scientific commuPartner in 14 EU funded
nity to use the mouse to develop a
projects since 2002
complete functional annotation of
110 Staff members
the human genome and to employ
this to better understand human
diseases and their underlying physiological and pathological basis. <
The ICS is a national infrastructure closely linked to the
IGBMC. Its mission is to :
● provide a service platform combining a large scale capacity for generating mouse mutants followed by subsequent high-throughput and comprehensive phenotypic
analysis of the animals
● facilitate access to engineering, analysis and distribution of mouse models for the scientific community
● initiate and advance relevant in-house research and
development programs to support the activities of ICS
in the domains of mutagenesis, transgenesis, phenotyping, bioinformatics, and data analysis.
● promote training both internally and for users in order
to guarantee the most efficient procedure in compliance
with ethics and animal welfare.
● be a reference centre for mouse functional genomics
and preclinical research
101
bioinformatiCS
¨ Previously, we worked mainly on genome sequences, however
today the field of investigation has widened. There is not only one,
but many Bioinformatics.¨ F. Plewniak
platforms
The IGBMC Bioinformatics technical platform platform provides bioinformatics resources including up-to-date databases,
bioinformatics software, efficient computer
systems, large storage capacity and expertise
capable of addressing biological problems
from basic sequence analysis to integrative and
high-throughput computational biology.
In sympathy with the IGBMC’s research interests, we are mainly involved in comparative
genomic and bioinformatic studies of transcription related to research on human pathologies, such as cancer or genetic diseases. This
includes promoter analysis, for example, phylogenetic foot-printing, in relation to transcriptomics data analysis, as well as studies of
evolutionary events or mutation effects in human and animal model organisms.
The platform is located within the IGBMC
premises in close proximity to the biologists.
The platform benefits from a particularly favo-
rable environment to develop its expertise both
in biology and computer science. The dual
competence of its staff members permits the
offering of a high standard of expertise in bioanalysis, as well as database or software development services. For all projects
we guarantee that the underlying
ISO 9001
scientific problem is properly
understood and addressed using
IBiSA
appropriate solutions.
35 projects/year
The platform is a member of the
Réseau National des plate-formes
5 Staff members
Bio-Informatiques (ReNaBi) and
was recognized as an operational
platform by IBiSA (Infrastructures Biologie Santé et Agronomie) in 2009. The Bioinformatics platform
Quality Management System according to
ISO 9001 norm was certified in June 2007. <
Access to bioinformatics resources
The bioinformatics resources provided by the platform include:
• Over 30 public databases (Genbank, Uniprot, Protein Data
Bank,Unigene,...)
• All prokaryotic complete genomes available from the
NCBI
• 41 selected eukaryotic complete genomes
• Locally developed and third party software
Expertise in bioinformatics and bio-analysis
This activity includes both short-term consultancy projects
and the participation of the platform as a partner to longterm funded projects.
Research and development
Apart from the above services, an important mission of the
platform is to develop innovative solutions for bioinformatics and bio-analysis questions.
103
HIGH-THROUGHPUT cell-based SCREENING
"High throughput cell-based screening technologies accelerate the phase
of identification of genes responsible for a particular phenotype or response,
by delivering an immediate functional characterization" L. Brino
The IGBMC High-Throughput Cell-based
Screening platform, created in 2006, is one of the
major high-throughput RNAi screening facilities in
France. We participate in the global project realization beginning with: cellular process optimization,
assay miniaturization, image analysis and development even before the screening campaign is started. Primary and secondary phenotype screening
and validations are performed by the facility. We
are equipped with a BSL2+ biologicalcontainment
facility for mammalian cell culture, high-throughput cell transfection and post-processing cell manipulation. Currently, assay read-outs are performed
either on the fully automated GE Life Sciences
INCELL1000 analyzer or the Berthold High
throughput MITHRAS LB940. Together with
the IGBMC Bioinformatics platform, we have
developed a robust biostatistical tool (RReportGenerator software) for the analysis of large cellular
multiparameter datasets as well as downstream
data enrichment solutions for comprehensive phe-
notype analyses. So far, we have performed more
than ten RNAi-based screening projects and we are
currently investigating the chromatin function in
DNA damage repair processes. Our siRNA libraries target diverse human and mouse gene subsets
such as the kinome/phosphatome or the druggable genome
IBiSA in process
and we have recently acquired
ISO 9001
a Qiagen human genome-wide
in process
siRNA library. The platform is
65,000 analyses
developing a Quality Managein 2009
ment System (ISO9001 norm)
and has been identified by IBiSA
5 Staff members
for the coming round of qualification and support. The platform is largely open to French
and foreign academic laboratories. <
• Expertise in mammalian cell transfection and RNAi
screening design.
• Participates in the preparation of applications for
research projects that aim to conduct phenotypic
screening.
• Develops innovative high-throughput cell-based applications.
• Participates in the development of high-content analysis solutions in biostatistics and bioinformatics.
• Strengthens and accelerates the approach “From
Genes to Drugs”.
imaging and microscopy
¨ Over 20 years, the imaging service has acquired a unique expertise.
Inventive and creative, it develops prototypes that can be industrialized. ¨
J-L Vonesch
The Imaging Center was created in 1992 to deal
with the increasing demands and the complexity of
biological imaging at the IGBMC. Recognized as an
IBiSA platform, this facility is not only devoted to
the IGBMC but reaches out to both the local and
French scientific community. The Imaging staff, organized as two groups for light and electron microscopy, has complementary expertise and experience
that ranges from biology and physics to computing.
This experience and expertise allows the platform to
offer a wide variety of equipments and approaches
both in terms of service, teaching and development.
The light microscopy group (7 engineers) offers an
open access to a range of imaging systems, such
as epifluorescent and confocal microscopes and
macroscopes. Image analysis stations are also offered
to the users of the platform. The specialists of the
group assist the researchers in more complex experiments where specific expertise is needed, such as Ftechniques (FRAP, FRET/FLIM). More than 80%
of the experiments in the facility are performed on
living samples with specific setups tailored for functional imaging, time lapse microscopy, and fast multiphoton and confocal imaging.
The electron microscopy group (4 engineers and a
technician) has extensive experience in studying the
ultrastructure of various cell types and tissues in normal and pathological conditions. With an expertise
in sample preparation ranging from conventional
techniques to the use of cryomethods, such as high pressure
IBiSA
freezing and freeze-substitution,
100 projects per year
the facility can process almost any
40 imaging systems
type of biological sample, from
• 10 confocal
cellular extracts to tissue biopsies.
microscopes
Besides the ultrastructural analy• 2 TEM,
• 1 SEM
sis, the group also performs protein localization at high resolution
25-30 publications
by immuno EM labeling.
per year
The two groups also offer com13 Staff members
bined and integrated approaches
such as correlated light and electron microscopy.<
The Imaging Center is an open facility that offers integrative imaging approaches to trained and untrained users:
• Development of new tools and protocols in collaboration
with research teams, to address challenging biological
questions, such as micromanipulation and live imaging,
photo-ablation, correlative light and electron microscopy.
• Further development of the ultra-wide-field photonic
imaging and confocal macroscope designed at the Center, to visualize and quantify biological processes at the
centimeter scale.
• Industrial partnership (Leica Microsystems, COMAT).
• Continuum of imaging techniques between light and
electron microscopy (confocal microscopy and macroscopy, infra and far-red two photon microscopy, fast confocal
microscopy, ultrastructural analysis).
• Image processing and analysis
• Teaching programs and training workshops at the University with national and international organizations.
105
MICROARRAYs & DEEP SEQUENCING
" Our techniques allow the study of genetic and molecular differences
between the normal and pathological states." C.Thibault
The IGBMC Microarray and Deep Sequencing platform, created in 2000, is one of the
major microarray facilities in France. We are
equipped with Affymetrix and Agilent microarray technologies and we run 1,500 to
2,000 arrays annually for a wide variety of
transcriptomic and genomic applications.
In October 2008, the platform invested in
high-throughput sequencing technology, and
implemented an Illumina GAII sequencing
system. Since its installation, we have completed more than 50 projects and generated
over 3 terabases of sequences. Importantly,
our platform also provides support to researchers for data analysis. Indeed, we have the
expertise (statistic and bioinformatic) and the
infrastructure (server and dedicated software)
to conduct microarray and sequencing data
analysis.
Our platform is open to French and foreign
academic laboratories, and data obtained have
contributed to numerous publications, many
of them in the best international journals (82
publications as of February 2010). The platform has been involved in several large national programs, such as the Tumor Identity
Card (CIT) program from the Ligue Nationale Contre le Cancer, and the
RESOGEN program from the
French Center for Genomic ISO 9001
Research. It has also been quaIBiSA
lified as ¨ National platform ¨
by the ¨ Réseau Inter-Organism 150 Projects
¨ (RIO) and also by the IBISA per year
since 2003. Lastly, because the 11 Staff members
platform has heavily invested in
quality, it became one of the first
French technology platforms to
obtain the ISO9001 certificate
in 2007, which was renewed in 2010. <
Our mission is to provide researchers with state of the
art high throughput technologies for analysing gene expression and regulation. We provide array based applications such as Affymetrix microarrrays for gene expression profiling, miRNA expression, SNP genotyping, and
CNV analysis. We also provide Illumina high throughput
sequencing applications such as ChIP-seq, RNA-seq and
whole genome or targeted re-sequencing.
Full services involve all steps from quality checks of starting material, labelling and hybridisations for array applications, library preparations and sequencing, and data
analysis. Support for in-depth bioinformatics and statistical data analysis for array and sequencing approaches
is also available.
STRUCTURAL BIOLOGY & GENOMICS
¨ This platform is the technological backbone for the production
and characterization of functional complexes and will be an essential
player in the future challenges in structural cell biology.¨ D. Busso
The focus of the Structural Biology and Genomics
platform (SBGP) is to provide technological resources to investigate complex biological systems,
that range from single proteins to assemblies of
proteins and nucleoprotein complexes. Ultimately this will contribute to an integrated view of
cellulars systems. The objective of the platform is
to accelerate the pace of discoveries by providing
integrated high-throughput approaches to investigate eukaryotic macromolecular complex systems
related to human health by using a continuum of
state-of-the-art technologies. These technologies
range from gene cloning to structure determination and ultimately to cellular resolution. The
SBGP was registered by the RIO coordination in
2003 and was confirmed in 2006 and 2008 by IBiSA. This national label implies that the platform
is open to the scientific community and is implicated in the important mission of training both
scientists and technical staff within collaborative
projects. Moreover, the tight synergies between
the SBGP and the IGBMC facilities (Bioinformatics, Mass Spectroscopy, Cell Imaging) create
an attractive scientific center for academic and
industrial researchers. Thus, providing integrated
structural and functional studies
on systems that are important to
IBiSA
the understanding of biological
pathways and human diseases.
HTP procedures
A major commitment of the
Quality statements
SBGP is to implement cutting
edge technologies and to deveEuropean networks
lop methodologies for protein
8 Staff members
production and characterization
that contribute to the technological backbone of the Strasbourg
node in the European Integrative
Structural Biology Infrastructure
Program (INSTRUCT). <
The SBGP offers high-level support to its users, ranging
from gene cloning to structure determination. It notably
makes use of the following methods and cutting edge
technologies:
• Automated cloning (Gateway, SLIC, restriction, …) and
mini-expression screening protocols using Tecan liquid
handling systems.
• Protein production in various expression systems (bacteria, insect cells, mammalian cells).
• Parallel purification of proteins, nucleic acids and their
complexes using Akta Xpress and Akta Purifier FPLC
chromatographic systems.
• Macromolecule characterization using different biophysical methodologies (DLS, AUC, ITC).
• Automated crystallization of macromolecules using a
Cartesian nano-volume liquid handling robot.
• Structure elucidation on crystals (X-rays with Micromax
rotating anode from Rigaku) or in solution (EM, SAXS;
NMR).
So far, the platforms contributions have been published
in ten articles.
107
Core facilities
Core facilities
• Mass Spectrometry Facility
• Core service for Flow Cytometry
& Fluorescence-Activated
Cell Sorting
Claudine Ebel
• Animal house
Head Animal House: Elisabeth Metzger
Responsible Sanitary: Armelle Van Es
The Animal House, which includes the
ICS, serves around 25 research groups at
the IGBMC and accommodates approximately 105,000 mice. Other than its animal
maintenance roles and the technical assistance
granted to researchers, the animal house has
specific activities such as the importation and
exportation of animals, the rederivation and
the cryopreservation of mouse lines.
• Cell Culture Facility
Betty Heller
The facility maintains more than 2,000 cell
lines which include normal and tumoral cell
lines from several origins. It produces 5,000
T-75 cm2 cell flasks, freezes 6,000 cryotubes,
and prepares 5,000L of media per year.
The facility also manages a L3 laboratory for
virus experiments.
This service allows investigators to perform
multi-parameter flow cytometry analysis and
sorting of cells and particles in liquid
suspension based on size, granulosity and color of fluorescence. Two state-of-the-art analyzers (FACS, Calibur for 4 color analysis, LSR
II for 15-color analysis) and two high-speed
sorters (FACSVantage SE option DIVA with
8 color capacity, FACSAria II with 15 color
capacity) are available to IGBMC scientists
and the Strasbourg scientific community.
The core service also provides protocols and
procedures for numerous applications.
• Histopathology &
Embryology Service
Stéphanie Muller
Mouse models are readily accessible to
post-mortem analyses at any time during
the course of a disease, including the stages
preceding its clinical onset. Thus, histological
analysis of mutant and/or treated mice
provide a powerful means to draw on
pathophysiological scenarios.
•Transgenic Facility
Adeline Page
Andrée Dierich
The mass spectrometry facility provides the
IGBMC community with standard and dedicated
proteomic analyses for the characterization of
proteins, including recent technological
developments. Among others, this includes protein identification, protein modification detection
and measurement of the molecular masses of
intact protein and non-covalent complexes. The
service is equipped with two ionic trap mass spectrometers (LTQ XL and LTQ Velos), an
ESI-TOF mass spectrometer for analysis of
molecular masses (MicrOTOF Focus) and a
MALDI-TOF (Reflex IV) apparatus.
The Transgenic Facility generates mouse
models for in vivo gene function analysis by:
• Classical transgenesis (micro-injection of
transgenes)
• Homologous recombination in mouse
embryonic stem cells.
• Tetraploid aggregation chimeras
• Production of monoclonal &
polyclonal antibodies
Mustapha Oulad-Abdelghani (monoclonal)
Gilles Duval (polyclonal)
Our service produces up to 40 monoclonal and
200 polyclonal antibodies per year for in-house
and external teams. The service can use recombinant proteins or polypeptide coupled to ovalbumine for immunization of the mouse, rabbit or
rat. It also provides advice to design recombinant
or synthetic antigens suitable to specific application.
• The Baculovirus Service
Isabelle Kolb-Cheynel and Nathalie Troffer-Charlier
The Baculovirus Expression Facility provides
investigators with equipment, expertise and
custom services for protein production in insect
cells. Services include: generation, amplification
and maintenance of high-titer baculovirus stocks,
analytical scale productions for protein-protein
interaction studies, optimization of protein
expression and preparative scale productions.<
• Peptide synthesis
Pascal Eberling
Peptide synthesis is performed on a 433A
peptide synthesizer (ABI), using Fmoc chemistry.
Crude peptides are purified by inverse phase
HPLC. End products are checked and
characterized by HPLC and mass spectrometry.
109
Facts & figures
Facts & figures
Statistics until June 30th
A major part of IGBMC staff (62%) is located within
research teams: these are statutary scientists, post-docs,
PhD students and technical staff.
Engineers and technicians with high levels of expertise
are employed on our platforms and our core facilities al-
A major part of IGBMC’s funding (87%) comes through
research grants. Our researchers apply to charities (AFM,
FRM...), national public funding agencies (ANR,
INCA...) and/or European or International Programmes
(FP7, NIH, HFSP...). The other 13% comes from institutional funding (CNRS-Inserm-Université de Strasbourg).
Research funding
12%
3% 5%
Staff allocations
(except ICS)
13%
15%
Institutional funding
3%
12%
Public funding
18%
46%
Charities
Research teams
European Union funding
IGBMC common
International support
Platforms
Industrial contracts & licences
Core Facilities
Investments & services
ICS
5%
6%
Nationalities of staff scientists
Distribution of statutary
and non-statutary staff
Distribution of staff scientists
7%
32%
17%
33%
67%
lowing the pooling of resources: they represent 26% of
our staff and work for both internal and external research
teams and/or industrial laboratories. The remaining 12%
cover administrative (Purchasing, Human Resources, Finance...) , IT Service and Building Maintenance.
13%
12%
33%
55%
62%
The IGBMC is an international center with 48 different
nationalities represented among its personnel. All activities in the Institute are carried out in English.
768 employees (including ICS)
43 groups
4 research programmes
5 platforms + ICS
31%
Non-Statutary staff
Group leaders
PhD students
Statutary staff
Staff scientists
Master students
France
More than 200 publications/year
EU (except France)
57 million Euros budget
Others
14,000 m² of laboratories
Post-docs
111
staff scientists
Development & Stem Cells
Coordinator :
LABOUESSE Michel
Assistant: BRONNER Sylvianne
DOLLE Pascal
Role of retinoic acid in mouse
development
Scientists
BLOCH-ZUPAN Agnès
DOLLE Pascal
KREZEL Wojciech
RHINN Muriel
Postdoctoral fellows
PASCHAKI Marie
PhD Students
ETTER Guillaume
KRZYZOSIAK Agnieszka
LAUGEL Virginie
RATAJ Monika
Engineers/Technicians
FRAULOB Valérie
SCHUHBAUR Brigitte
Master Student
SCHUH Mélanie
HEITZLER Pascal
Genetic and molecular analysis
of early neurogenesis in Drosophila melanogaster
Scientists
HEITZLER Pascal
Postdoctoral fellows
BIRYUKOVA Inna
Engineers/Technicians
ACKERMANN Claudine
Master Students
CHOONG Kee-Fong
SALLOUM Anastasia
JARRIAULT Sophie
In vivo analysis of cellular
plasticity in C. elegans
Scientists
JARRIAULT Sophie
Postdoctoral fellows
AHIER Arnaud
HAJDUSKOVA Martina
ZURYN Steven
PhD Students
DANIELE Thomas
Engineers/Technicians
GEORGES-LABOUESSE Elisabeth
FISCHER Nadine
Integrin function and signaling in Master Students
tissue morphogenesis, integrity
Marie-Charlotte Morin
and homeostasis
Scientists
LABOUESSE Michel
DE ARCANGELIS Adèle
Forces and signals in tissue
GEORGES-LABOUESSE Elisabeth
morphogenesis
PhD Students
Scientists
TOSSE Lindzy
GALLY Christelle
Engineers/Technicians
LABOUESSE Michel
PFISTER Véronique
QUINTIN Sophie
SIEBERT Stéphanie
Postdoctoral fellows
KOLOTUEVA Irina
GIANGRANDE Angela
OSMANI Naël
Cellular and molecular
ZHANG Huimin
mechanisms of nervous system
PhD Students
differentiation
APAYDIN Ahmet
Scientists
Engineers/Technicians
GIANGRANDE Angela
RODRIGUEZ David
Postdoctoral fellows
Master Student
KOMONYI Orban
PASTI Gabriella
LANEVE Pietro
POPKOVA Anna
MARK Manuel/GHYSELINCK
PhD Students
Norbert
BERZSENYI Sara
Retinoic acid signalling
ERKOSAR Berra
pathways driving stem sperFLICI Hakima
matogonia ontogenesis and
KARATAS Omer Faruk
differentiation
KUMAR Arun
Scientists
Engineers/Technicians
GHYSELINCK Norbert
ARBOGAST Nadine
MARK Manuel
DIEBOLD Céline
Postdoctoral fellows
MURA Carole
GELY PERNOT Aurore
PAPALINI Giulia
JACOBS Hugues
PhD Students
GRADWOHL Gérard
RAVERDEAU Mathilde
Control of endocrine cells
Engineers/Technicians
differentiation in the pancreas
DENNEFELD Christine
and intestine
FERET Betty
Scientists
KLOPFENSTEIN Muriel
GRADWOHL Gérard
Master Student
MELLITZER Georg
BOUROUINA Imane Rym
Postdoctoral fellows
BEUCHER Anthony
MERLE Carole
PhD Students
NIVLET Laure
PICCAND Julie
Engineers/Technicians
MEUNIER Aline
POULET Martine
Master Student
STRASSER Perinne
POURQUIE Olivier
Development of muscle and
vertebrae
Scientists
KNOCKAERT Marie
POURQUIE Olivier
REBAGLIATI Michael
Postdoctoral fellows
BENAZERAF Bertrand
CADETE VILHAIS NETO Gonçalo
CHAL Jérôme
MARUHASHI Mitsuji
OGINUMA Masayuki
SU Cheng Wen
WAHL Matthias
PhD Students
ANTONI Bernadette
BERA Agata
DE MOT Laurane
DENANS Nicolas
KROL Aurélie
Engineers/Technicians
DALI Soraya
GARNIER Jean-Marie
KENNEDY Leif
MONCUQUET Philippe
PACE Jennifer
PLASSAT Jean-Luc
TASSY Olivier
Master Student
GUENNOUN Rym
RIVELINE Daniel
Laboratory of Cell Physics
Scientists
RIVELINE Daniel
Engineers/Technicians
HOEL Antonin
TORRES-PADILLA Maria Elena
Epigenetics and cell fate in early
mammalian development
Scientists
TORRES PADILLA Maria Elena
Postdoctoral fellows
BURTON Jonathan Adam
FADLOUN Anas
MIYANARI Yusuke
PhD Students
SANTENARD Angèle
Engineers/Technicians
ZIEGLER-BIRLING Céline
Master Student
BENDER Ambre
VERMOT Julien
Mecano-genetic interplays and
embryonic morphogenesis
Scientists
VERMOT Julien
Postdoctoral fellows
GOETZ Jacky
MOJZISOVA Halina
PhD Students
HECKEL Emilie
Engineers/Technicians
GESCHIER Sandrine
ROTH Stéphane
VIVILLE Stéphane
Primordial germ cells’ ontogeny
Scientists
KOSCINSKI Isabelle
TELETIN Marius
VIVILLE Stéphane
Postdoctoral fellows
CELEBI Catherine
EL RAMY GHOSN Rosy
PhD Students
ELINATI Elias
JUNG Laura
Engineers/Technicians
ANDRE Cécile
SKORY Valérie
TROPEL Philippe
Master Students
FOSSARD Camille
TARABAY Yara
staff scientists
Functional Genomics & Cancer
Coordinator: DAVIDSON Irwin
Assistant: GASSERT Valerie
CHAN Susan/ KASTNER Philippe
Hematopoiesis and Leukemogenesis in the mouse
Scientists
CHAN Susan
KASTNER Philippe
KIRSTETTER Peggy
Postdoctoral fellows
CAI Qi
ORAVECZ Attila
PhD Students
APOSTOLOV Apostol
KAVERI Deepika
LE LAY Anne-Solen
MACIAS Beatriz Alejandra
MASTIO Jérôme
Engineers/Technicians
MARCHAL Patricia
Master Student
VESIN Rose-Marie
DAVIDSON Irwin
Structure and function of the
general transcription factor TFIID
Scientists
DAVIDSON Irwin
MARTIANOV Igor
MENGUS Gabrielle
Postdoctoral fellows
ALPERN Daniil
KOBI Dominique
LANGER Diana
PhD Students
BENHADDOU Ataaillah
CHOUKRALLAH Mohamed-Amin
MOUTIER Emmanuel
STRUB Thomas
Engineers/Technicians
MICHEL Isabelle
YE Tao
Master Student
URBAN Sylvia
EGLY Jean-Marc/COIN Frédéric
Genome expression and repair
Scientists
COIN Frédéric
COMPE Emmanuel
EGLY Jean-Marc
Postdoctoral fellows
EBEROVA Jitka
HASHIMOTO Satoru
LE MAY Nicolas
VELEZ-CRUZ Renier
VITRENKO Yakov
PhD Students
GIRAUDON Christophe
ILTIS Izarn
KORETS Roman
KRISTENSEN Hans-Ulrik
SINGH Amita
TRABOULSI Hussein
ZADORIN Anton
ZHOVMER Alexander
Engineers/Technicians
BRAUN Cathy
CATEZ Philippe
LARNICOL Annabel
MARTEL Fernand
PREVE Brigitte
Master Student
ZIANI Salim
GRONEMEYER Hinrich
From nuclear receptor action
to novel paradigms for cancer
therapy action
Scientists
GRONEMEYER Hinrich
Postdoctoral fellows
CESCHIN Danilo
KEDINGER Valérie
LUND Per
MENDOZA PARRA Marco
Antonio
PATTABHIRAMAN
Shankara-Narayanan
PAVET-PORTAL Valeria
PORTAL Maximiliano
PhD Students
KHANWALKAR Harshal
MUELLER Cathrin
VJETROVIC Jelena
WALIA Mannu Kamalraj
Engineers/Technicians
ERB Cathie
LIEB Michèle
PAULI Cecilia
VALLET Judith
VAN GOOL Wouter
YUJNOVSKY Irene
Master Students
BORIES Pierre
WEISS Mélanie
HAMICHE A .
Chromatin and epigenetic
regulation
Scientists
HAMICHE Ali
RAMAIN Catherine
RAMAIN Philippe
Postdoctoral fellows
DEPAUX Arnaud
OUARARHNI Khalid
PAPIN Christophe
PhD Students
OBRI Arnaud
OURY Julien
SHUAIB Muhammad
TRIPATHI Vivek
YETTOU Guillaume
Engineers/Technicians
DANIEL Dorothée
LOSSON R.
Scientists
CAMMAS Florence
Postdoctoral fellows
RICLET Raphaël
PhD Students
GRABER Céline
HERQUEL Benjamin
Engineers/Technicians
CERVINO Margarita
LEROUGE Thierry
METZGER/CHAMBON
Genetic dissection of nuclear
receptor signaling in the
mouse
Scientists
CHAMBON Pierre
KRUST Andrée
LI Mei
METZGER Daniel
Postdoctoral fellows
HUA Guoqiang
JIANG Hua
MUKHERJI Atish
SURJIT Milan
PhD Students
DUTEIL Delphine
GALI RAMAMOORTHY Thanuja
GANTI Krishna Priya
LEYVA CASTILLO Juan Manuel
Engineers/Technicians
BORNERT Jean-Marc
FRIEDMANN Laetitia
GARGOWITSCH Laëtitia
HENER Pierre
HUC Magali
MEYER Tania
Master Students
BAGCI Hakan
TALEB Fatima
REINA SAN MARTIN Bernardo
Molecular biology of B cells
Scientists
REINA SAN MARTIN Bernardo
Postdoctoral fellows
ROBERT Isabelle
ROTTNER Mathilde
PhD Students
JEEVAN RAJ Beena Patricia
MILOSEVIC Sara
SCHIAVO Ebe
Engineers/Technicians
HEYER Vincent
Master Student
OUBRAHAM Lila
RIO Marie-Christine /
TOMASETTO Catherine
Molecular and cellular biology
of breast cancer
Scientists
ALPY Fabien
DALI YOUCEF Nassim
RIO Marie-Christine
TOMASETTO Catherine
Postdoctoral fellows
BUACHE Emilie
PhD Students
DAGUENET Elisabeth
LEGUEUX François
ROUSSEAU Adrien
SIMOES David
TAN Jinxiang
Engineers/Technicians
STOLL Isabelle, technicienne
WENDLING Corinne, ingénieur
ROCHETTE-EGLY Cécile
Nuclear retinoic acid receptors
phosphorylation and Crosstalk with signaling pathways
Scientists
EGLY Cécile
Postdoctoral fellows
ALTANOUZY Ziad
DUONG Vanessa
PANKOTAI-BODO Gabriella
PhD Students
FERRY Christine
PISKUNOV Aleksandr
SAMARUT Eric
Engineers/Technicians
GAOUAR Samia
LUTZING Régis
SERAPHIN Bertrand
Protein networks and complexes regulating eukaryotic
mRNA decay
Scientists
MAUXION Fabienne
SERAPHIN Bertrand
Postdoctoral fellows
DREUMONT Natacha
GAS LOPEZ Maria
KOLESNIKOVA Olga
PhD Students
RISPAL Delphine
VAN DEN ELZEN Antonia
Engineers/Technicians
FAUX Céline
GAUDON-PLESSE Claudine
MULLER Benjamin
SOUTOGLOU Evi
Cell Biology of genome
integrity
Scientists
SOUTOGLOU Evi
Postdoctoral fellows
NAGY Zita
PANKOTAI Tibor
PhD Students
HOFFBECK Anne-Sophie
LEMAITRE Charlène
Engineers/Technicians
BONHOMME Céline
FURST Audrey
TORA Laszlo
Chromatin modifications and
regulation of gene expression
during differentiation
Scientists
DEVYS Didier
TORA Laszlo
Postdoctoral fellows
BALLARINO Monica
FOURNIER Marjorie
HELMRICH Anne
KARMODIYA Krishanpal
UMLAUF David
PhD Students
BONNET Jacques
GYENIS Akos
KREBS Arnaud
LANG Guillaume
RISS Anne
Engineers/Technicians
SCHEER Elisabeth
STIERLE Matthieu
WASYLYK B.
Molecular and cellular biology
of cancer
Scientists
WASYLYK Bohdan
PhD Students
LI Yadong
SEMENCHENKO Kostyantyn
Engineers/Technicians
WASYLYK Christine
Attached researcher:
DU MANOIR Stanislas
Integrated Structural Biology
Coordinator : SCHULTZ Patrick
Assistant: NEY Anne
CAVARELLI Jean
Structural biology of epigenetic
targets
Scientists
CAVARELLI Jean
CURA Vincent
ROMIER Christophe
WURTZ Jean-Marie
Postdoctoral fellows
HASSENBOEHLER Pierre
MAREK Martin
PhD Students
DIEBOLD Marie Laure
LEPROULT Emeline
LIENHART Yann
MAILLIOT Justine
Engineers/Technicians
TROFFER-CHARLIER Nathalie
DEJAEGERE-STOTE Annick
Biocomputing
Scientists
DEJAEGERE-STOTE Annick
STOTE Roland
Postdoctoral fellows
BROCHET Xavier
SCHWARZ Benjamin
PhD Students
AMAL Ismail
FERRARIO Maria Giovanna
KIEFFER Bruno
Biomolecular Nuclear Magnetic
Resonance
Scientists
DELSUC Marc-André
KIEFFER Bruno
LEBARS Isabelle
Postdoctoral fellows
RAMIREZ RAMOS Juan Ramon
QUINTERNET Marc
PhD Students
TANTY Matthieu
Engineers/Technicians
LING Claude
KLAHOLZ Bruno
Large complexes involved in
gene expression
Scientists
KLAHOLZ Bruno
OURJOUMTSEV Alexandre
Postdoctoral fellows
KRISHNAGIRI
VENKATASUBRAMANIAN Srividhya
MALETTA Massimiliano
MANICKA Sankar Narayanan
MYASNIKOV Alexander
ORLOV Igor
SIMONETTI Angelita
PhD Students
TORCHY Morgan
Engineers/Technicians
HAZEMANN Isabelle
MENETRET Jean-François
113
staff scientists & PLATFORMS
MORAS Dino
Expression of genetic information
Scientists
BILLAS-MASSOBRIO Isabelle
DOCK-BREGEON Anne-Catherine
MORAS Dino
POTERSZMAN Arnaud
ROCHEL-GUIBERTEAU Natacha
RUFF Marc
Postdoctoral fellows
ABDULRAHMAN Wassim
ANTONY Pierre
BRELIVET Yann
LEVY Nicolas
OSZ-PAPAI Judit
RADU Laura
TAKACS Maria
PhD Students
ALBOU Laurent Philippe
MAILLOT Benoît
MARTINEZ ZAPIEN Denise
SCHAETZEL Aurélie
UCHIKAWA Emiko
Engineers/Technicians
EILER Sylvia
PELUSO-ILTIS Carole
POCH Olivier
Evolutionary systems biology
Scientists
POCH Olivier
LECOMPTE Odile
MULLER Jean
THOMPSON Julie
WICKER Nicolas
Postdoctoral fellows
NGUYEN Ngoc Hoan
PhD Students
ANNO Yannick-Noël
ANIBA Mohamed Radhouane
LINARD Benjamin
LUU Tien Dao
Engineers/Technicians
MOULINIER Luc
POIDEVIN Laëtitia
RIPP Raymond
SCHULTZ Patrick
Architecture of
Nucleoprotein Systems by 3-D
Electron Microscopy
Scientists
DRILLIEN Robert
LAMOUR Valérie
SCHULTZ Patrick
Postdoctoral fellows
PAPAI Gabor
PRADEAU AUBRETON Karine
PhD Students
KIZILYAPRAK Caroline
PAPILLON Julie
Engineers/Technicians
CRUCIFIX Corinne
DURAND Alexandre
RUHLMANN Christine
SIMONI Albin
SPEHNER Danièle
YUSUPOV Marat
Ribosomes
Scientists
JENNER Lasse Bohl
YUSUPOV Marat
YUSUPOVA Gulnara
Postdoctoral fellows
BEN SHEM Adam
DEMESHKINA Natalia
MELNIKOV Sergey
PhD Students
GARREAU DE LOUBRESSE Nicolas
Engineers/Technicians
DUCLAUD Sylvie
Attached Scientists:
PODJARNY Alberto
COUSIDO-SIAH Alexandra
MITSCHLER André
Translational medicine &
Neurogenetics
Coordinator : KIEFFER Brigitte
Assistant: BRONNER Sylvianne
CHARLET-BERGUERAND Nicolas
Physiopathology of the RNA
gain-of-function diseases
Scientists
CHARLET BERGUERAND Nicolas
Postdoctoral fellows
SELLIER Chantal
PhD Students
FREYERMUTH Fernande
RAU Frédérique
Engineers/Technicians
FISCHER-HUMMEL Marie-Christine
FUGIER Charlotte
HICKEL Pierre
FABRE Jean-Etienne
Atherosclerosis and thrombosis
Scientists
FABRE Jean-Etienne
Postdoctoral fellows
BOUCHAREB-DAHOU Rihab
SLIMANI Farid
Engineers/Technicians
TILLY Peggy
HANAUER André/
MANDEL Jean-Louis
Mechanisms of monogenic
forms of mental retardation
Scientists
HANAUER André
MANDEL Jean-Louis
MOINE Hervé
Postdoctoral fellows
BOHM Johann
PhD Students
MEHMOOD Tahir
SCHNEIDER Anne
TABET Ricardos
VASLI Nasim
Engineers/Technicians
PANNETIER Solange
FLATTER Eric
HAUMESSER Nicolas
HERAULT Yann
Physiopathology of aneuploidy,
gene dosage effect and Down
syndrome
Scientists
BRAULT Véronique
HERAULT Yann
Postdoctoral fellows
MARECHAL Damien
RAVEAU Matthieu
SALEH Abdelsalam
Engineers/Technicians
CHEVALIER Claire
DUCHON Arnaud
NALESSO Valérie
KIEFFER Brigitte
The opioid system and brain
function
Scientists
BECKER Jérôme
BEFORT Katia
GAVERIAUX-RUFF Claire
KIEFFER Brigitte
MASSOTTE Dominique
OUAGAZZAL Abdel-Mouttalib
ROUX Michel
STEPHAN Aline
Postdoctoral fellows
DARCQ Emmanuel
LE MERRER Julie
NOZAKI TAKAHASHI Chihiro
PETERSCHMITT Yvan
SEBAI Sarra
PhD Students
CHU SIN CHUNG Paul
DEL BOCA Carolina
DENIZ Sercan
FAGET Lauren
GARDON Olivier
LUTZ Pierre-Eric
REZAI Xavier
WEIBEL Raphaël
Engineers/Technicians
ERBS Eric
FILLIOL Dominique
KOEBEL Pascale
MATIFAS Audrey
REISS David
ROBE Anne
KOENIG Michel
Recessive ataxias
Scientists
KOENIG Michel
Postdoctoral fellows
ASSOUM Mirna
Engineers/Technicians
DROUOT Nathalie
LAPORTE Jocelyn
Mechanisms of neuromuscular
disease
Scientists
LAPORTE Jocelyn
Postdoctoral fellows
COWLING Belinda
D’ALESSANDRO Manuela
HNIA Karim
KOUTSOPOULOS Olga
ROYER ZEMMOUR Barbara
PhD Students
AMOASII Leonela
TOSCH Valérie
ZIVKOVIC Ivana
Engineers/Technicians
KOCH Catherine
KRETZ Christine
PUCCIO Hélène
Biology and Physiology of
recessive ataxia
PUCCIO Hélène
Postdoctoral fellows
BOYER Frédéric
MARTELLI Alain
TESCHNER Julia
WATTENHOFER-DONZE Marie
PhD Students
COLIN Florent
LICITRA Floriana
SCHMUCKER Stéphane
Engineers/Technicians
REUTENAUER Laurence
VAUCAMPS Nadège
Master
HICK Aurore
TROTTIER Yvon
Pathogenic mechanisms of
polyglutamine expansion diseases
Scientists
MERIENNE Karine
TROTTIER Yvon
Postdoctoral fellows
KLEIN Fabrice
PhD Students
DAVRANCHE Aurélien
GOULA Agathi-Vasiliki
KARAM Alice
Engineers/Technicians
WEBER Chantal
Master
EL KHOURY Rita
Technical support & administration
PLATFORMS
Bioinformatics
PLEWNIAK Frédéric
BIANCHETTI Laurent
GEOFFROY Véronique
RAFFELSBERGER Wolfgang
SIGUENZA Sophie
OULAD-ABDELGHANI
Mustapha, Antibodies Monoclonal
ANDRES Valérie
JUNG Nicole
Microarrays and Deep
Sequencing
THIBAULT-CARPENTIER Christelle
ALUNNI Violaine
BAMBA Géraldine
COLAS Ingrid
DEMBELE Doulaye
HANAUER Antoine
HEROUARD-MOLINA Cathy
JOST Bernard
KEIME Céline
LE GRAS Stéphanie
VICAIRE Serge
TROFFER-CHARLIER Nathalie,
Baculovirus
KOLB-CHEYNEL Isabelle
VIALLE Chantal
Structural Biology and Genomics
Platform
BUSSO Didier
BIRCK Catherine
GRANGER Florence
LITT Alain
MCEWEN Alastair
POUSSIN-COURMONTAGNE
Pierre
SALIM Loubna
TROESCH Edouard
Imaging Center
VONESCH Jean-Luc
HENTSCH Didier
SCHWAB Yannick
MESSADDEQ Nadia
BOEGLIN Marcel
DEISS Alexandre
FAUNY Jean-Daniel
HERGUEUX Josiane
KESSLER Pascal
KOCH Marc
LUTZ Yves
SPIEGELHALTER Coralie
WEICKERT Jean-Luc
High Throughput Cell-based
Screening Platform
BRINO Laurent
FISCHER Benoit
FROIDEVAUX Laure
MOUNE-DIMALA Martin
WEISS Amélie
Cores Facilities
VAN ES Armelle,
Veterinary
METZGER Elisabeth,
Head of Animal House
BLONDELLE Asmae
CHRIST Lydia
DELAPORTE Claude
DIETRICH Holly
DUFOUR Stephane
EISENMANN Aurélie
FALCONE Sylvie
GENDRON Michaël
HACHEM Rabiaa
HIRLIMANN Anne-Lise
JAWAD Agouna
KHADRAOUI Hafid
KORCHI Hafid
KORCHI Nordine
MAGNANT William
MEMEDOV Fatima
POIROT Martine
RICHERT Mourad
SIEGEL Sabine
VINCENT Alexandre
ZINK Nicolas
DUVAL Gilles, Antibodies Polyclonal
MEMEDOV Djemalj
HELLER Betty,
Cell culture & Cell Bank
BOSSENMEYER Patricia
CHRISTOFFEL Ghislaine
FELS Karine
FERANDEL Noëlle
MASTIO Leslie
RIESTERER Hélène
SIGNOUR Aline
PAGE Adeline,
Head of Mass spectrometry
CHAVANT Virginie
RUFFENACH Frank
EBEL Claudine,
Cell Sorting
EBERLING Pascal,
Peptide synthesis
ICS
HERAULT Yann, ICS Director
SORG-GUSS Tania, Technical
Director
ICS Management Support
BLONDELLE Eric
CHEBBOUB Djaouida
FRICKER Bastien
NAGRE Isabelle
PENSAVALLE Joëlle
RIO-ZENNER Fanny
SELLOUM Mohammed
ICS Bioinformatics
VASSEUR Laurent,
Head of Bioinformatics
DEBOUZY Guillaume
LEBLANC Sophie
MORO Anne-Isabelle
ICS Genetic Engineering and
Model Validation
PAVLOVIC Guillaume, Head
of Mutagenesis, Transgenesis
& Molecular Phenotyping
Department
AUGE Fabrice
BIRLING Marie-Christine
CARADEC Claudia
CAYROU Pauline
CHARTOIRE Nathalie
DIERICH Andrée
DREYER Dominique
EGLINGER Yolande
ERBS Valérie
ESSABRI Karim
HELMSTETTER-VERDOT Cindy
JACQUOT Sylvie
KLEISS Charlotte
LINDNER Loïc
LORENTZ Romain
LUPPI Laurence
MERTZ Annelyse
QUEUCHE Danielle
ROTH Christelle
ROUSSEAU Valérie
SCHWOERER Marie-Jeanne
SEITZ Thierry
VENTEO Lydie
WALLERICH Sandrine
ICS Phenotyping
SORG-GUSS Tania, Head of
Phenotyping
AMANN Grégory
AUBURTIN Aurélie
AUVRAY Sandy
BECHAKRA Malik
BECKER Julien
BEDU Elodie
BUNZ Isabel
CES Aurélia
CHAMPY Marie-France
COMBE Roy
DING Thomas
EL FERTAK Lahcen
FOUGEROLLE Jean-Victor
GOETZ-REINER Patrice
GUIMOND Alain
KOUTSEFF Alexis
LALANNE Valérie
LE MARCHAND Elise
LECOCQ Muriel
LUX Aline
MEZIANE Hamid
MITTELHAEUSER Christophe
MONTIAL Marina
MOULAERT David
MULLER Stéphanie
PETER Emilie
PETIT-DEMOULIERE Benoît
PHAM THI BICH Hanh
POUILLY Laurent
RIET Fabrice
ROUSSEAU Stéphane
SUTTER-WOLTER Anne
TILLY Isabelle
WAGNER Christel
WEBER Bruno
WENDLING Olivia
ICS Mouse Facility
GONCALVES DA CRUZ Isabelle,
Veterinary
AYADI Abdelkader, Head of
Animal Facility Department
ALI-HADJI Dalila
ANDRE Philippe
BAM’HAMED Chaouki
BANQUART-OTT Nadine
BOUR Raphaël
BRIGNON Sophie
CHARLES Philippe
DELANGLE Benoît
EL FERTAK Leila
ENNAH Hamid
FISCHER Fabienne
FISCHER Natacha
GRUBER Frédéric
HEMMERLE Mathieu
KUJATH Christelle
KURTZ Caroline
LANTZ-CHAMPY Charlotte
LAEUFER Laurent
LEGEAY Sandrine
MELLUL Peggy
MOKNI Mourad
OHLMANN Thierry
SCHMITT Raphaël
SCHOEDEL Christophe
SEILER Stéphane
TOUBARI Chadia
UZUN Ibrahim
VINCENT Cindy
WALCH Laëtitia
WETZSTEIN Eric
WIECROCK Cyrille
WIECROCK Ludovic
ZANINELLO Fabienne
ZANINELLO Nathalie
Management
POURQUIE Olivier,
Director of IGBMC
BENSEL Nicolas,
Director of Logistic & Scientific
Operations
LUNKES Astrid,
Director of Scientific Affairs
SCHAEFFER Katell,
Director of Finance and
Administration
Management Assistance
BENARROCH Laurence
GONZALEZ Laetitia
KAUFFMANN Dominique
MEYER Estelle
SCHUBEL Françoise
THORNTON Laura
Reception
ACKER Evelyne
MENNA Martine
Human Ressources Department
PASQUIER Lydia, Head of
Human Ressources
ACKER Dominique
FISCHER Joëlle
LENTZ Brigitte
LESECQ Florence
METAIS Bénédicte
PETILLON Armelle
ROTH Catherine
TOUSSAINT Elisabeth
Communication
ESTEBAN-POURQUIE Silvia,
Head of Communication
BOUR Sandra
LEGRAND Elodie
Accounting/Controlling
RAMOND Marie-Jeanne,
Head of Finance
PINCHON Frédérique,
Head of Controlling
HOFFER Stéphane
Head of Accounting
CARBONNIER Laëtitia
GAUPP Cindy
GONTHIER Patricia
GRUFFAZ Agnès
HECKER Annick
MUNIER Brigitte
RACK Nicole
REGNERY Véronique
UFFLER Sylvie
Purchasing / Stock
MATHON Peggy
CHARLES Christelle
FASSEL Serge
GERBER Philippe
KIENZLER Elise
MULLER Catherine
REINE Valérie
REPIS Christian
SIGWALT Jessica
TAMAYO Sandrine
WETZSTEIN Eric
Technical Department
KOLB Claude,
Head of Technical Department
UNTEREINER Christophe,
Deputy/Technical Department
BEAUJEAN Frédéric
KUNTZ Pascal
LANG Doris
POIMBOEUF-MAHIEU Marc
SCHERMULY Jean-Claude
TANTON Patrick
TAUBERT Serge
VATTE Christophe
VONSCHEIDT Régis
WEIL Luc
House Maintenance
BINTEIN Cathy
BORSCHNECK Denise
CRABEY Karine
EL YAMANI Hassan
GREDLER Sylvie
HAOUALA Ilias
HEITZ Nadine
LAACHARI Mohammed
PERAL Louisette
PLANCHAT Catherine
SCHMITT Sylvie
STIEFFEL Emma
Valorisation/Grant
Management
BROOKS Steve
DAUZET Frédéric
Systems Architect/Administrator
MOUTAUX Tony
OFFNER Michel
IT Service
FRITZ Rémy, Head of IT Service
MALLOUH Véronique
CERDAN Stéphane
RONGVAUX Youry
SEITH Guillaume
TOUSSAINT Jean-Luc
UGE Serge
VERLEY Philippe
ZOUIOUIECH Agathe
Hygiene Safety
BIELLMANN Dominique
Library
MARTINA Hélène
PENEY Marie-Thérèse
115
prizes & distinctions
2010, Pediatric Pathology Research
Senior Prize 2009,
Jocelyn LAPORTE
2008, CNRS Bronze Medal,
Bruno KLAHOLZ
2010, Fondation Gairdner Prize
(Canada), Pierre CHAMBON
2008 Nominated Inventor of
the Year by the European Patent
Office, Bertrand SÉRAPHIN
2010, Eurosystem Young
Investigator Award,
Sophie JARRIAULT
2007, Madeleine Lecoq Prize,
Académie des Sciences,
Julie THOMPSON-MAALOUM
2009, Ligue Contre le Cancer
René et Andrée Duquesne Prize,
Jean-Marc EGLY
2007, Jules Martin Prize, Académie
des Sciences, Daniel METZGER
2009, INSERM Innovation Prize,
Jean-Marie GARNIER
2009, Fondation Schlumberger
pour la Recherche et l’Enseignement Prize, Sophie JARRIAULT
2009, Fondation pour la Recherche
Médicale Marguerite
Delahautemaison Prize,
Cécile ROCHETTE-EGLY
2009, Fondation pour la Recherche
Médicale Comité Alsace Scientific
Prize,
Maria-Elena TORRES-PADILLA
2009, Fondation pour la Recherche
Médicale Comité Alsace Scientific
Prize,
Bernardo REINA SAN MARTIN
2007, Prix de la Recherche de la
Fondation pour la Recherche Medicale Comité Alsace, Catherine
TOMASETTO
2006, Lacassagne Prize of Collège
de France, Filippo RIJLI
2006, EMBO Young Investigator,
Bruno KLAHOLZ
2006, Grand Prix de la Fondation
pour la Recherche Médicale,
Jean-Louis MANDEL
2005, Pediatric Pathology Research
Senior Prize, Hélène PUCCIO
2005, Jean Valade Award,
Johan AUWERX
2005 Cristal CNRS, Julie
THOMPSON-MAALOUM
2009, Académie Nationale de
Médecine Prize,
Jean-Louis MANDEL
2005, Helmholtz Humboldt Research Prize, Laszlo TORA
2009, Académie Nationale de
Médecine Henry et Mary-Jane
Mitjaville Prize, Jean-Marc EGLY
2005, Grand Prix Victor Noury,
Académies des Sciences ,
Olivier POURQUIÉ
2009, Académie des Sciences
Fondation scientifique franco-taïwanaise prize, Angela GIANGRANDE
2005, Edouard Van Beneden de
l’Académie Royale de Belgique,
Olivier POURQUIÉ
2009, Gutenberg Prize,
Bruno KLAHOLZ
2005, Grand Prix Ruban Rose de la
Recherche, Marie-Christine RIO
2008, Fondation pour la Recherche
Médicale Comité Alsace Scientific
Prize, Sophie JARRIAULT
2004, Richard Lounsbery, Académie des Sciences, France et USA
Brigitte KIEFFER
2008, Prix Jean et Madeleine
Schaeverbeke de la Fondation de
France, Adèle DE ARCANGELIS
2004, Prix Harland Winfield
Mossman en Biologie du Développement, American Association of
Anatomists, Olivier POURQUIÉ
2008, Dr. Jean Toy Prize, Académie
des Sciences, Hélène PUCCIO
2008, Charles-Louis de Saulses
de Freycinet Prize, Académie des
Sciences, Frédéric COIN
2004, Prix d’Honneur INSERM,
Pierre CHAMBON
2004, Paul Basset Award,
Catherine TOMASETTO
2004, IPSEN Neuronal Plasticity,
Jean-Louis MANDEL
2004, Ipsen Endocrine
communication and regulation,
Pierre CHAMBON
2004, Grand Prix INSERM 2004,
Jean-Marc EGLY
2004, ESHG Young Scientist
Award, Aurora PUJOL
publications Until June 2010
Amsen E, Alfred J, Pourquie O (2010)
The Node: a place to discuss, debate
and deliberate developmental biology.
Development 137: 2251
Anheim M, Fleury M, Monga B, Laugel V,
Chaigne D, Rodier G, Ginglinger E, Boulay
C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C,
Koenig M (2010) Epidemiological, clinical,
paraclinical and molecular study of a cohort
of 102 patients affected with autosomal
recessive progressive cerebellar ataxia
from Alsace, Eastern France: implications
for clinical management. Neurogenetics
11: 1-12
2004, Albert Lasker Award for
Basic Medical Research,
Pierre CHAMBON
Antony P, Sigueiro R, Huet T, Sato Y,
Ramalanjaona N, Rodrigues LC, Mourino
A, Moras D, Rochel N (2010) StructureFunction Relationships and Crystal
Structures of the Vitamin D Receptor
Bound 2alpha-Methyl-(20S,23S)- and
2alpha-Methyl-(20S,23R)-epoxymethano1alpha,25-dihydroxyvitamin D(3). J Med
Chem 53: 1159-71
2003, INSERM Innovation prize
«Methodology»,
Jean-Luc VONESCH
Arai Y, Gradwohl G, Kameda Y (2010)
Expression of neuropeptide Y and agoutirelated peptide in the hypothalamic arcuate
nucleus of newborn neurogenin3 null
mutant mice. Cell Tissue Res 340: 137-45
2004, Edwin B. Astwood Award,
Paolo SASSONE-CORSI
Audo I, Manes G, Mohand-Said S,
Friedrich A, Lancelot ME, Antonio A, Moskova-Doumanova V, Poch O, Zanlonghi X,
Hamel CP, Sahel JA, Bhattacharya SS, Zeitz
C (2010) Spectrum of rhodopsin mutations
in French autosomal dominant rod-cone
dystrophy patients. Invest Ophthalmol Vis
Sci 51: 3687-700
Ayoub, C, Wasylyk, C, Li Y, Thomas E,
Marisa L, Robé A, Roux M, Abecassis J,
de Reyniès A and Wasylyk B. 2010 ANO1
amplification and expression in HNSCC
with a high propensity for future distant
metastasis and its functions in HNSCC cell
lines. BJC, In press
Baret JC, Beck Y, Billas-Massobrio I,
Moras D, Griffiths AD (2010) Quantitative
cell-based reporter gene assays using
droplet-based microfluidics. Chem Biol
17: 528-36
Ben Khedher S, Zouari N, Messaddeq
N, Schultz P, Jaoua S. Overproduction of
Delta-Endotoxins by Sporeless Bacillus
thuringiensis Mutants Obtained by Nitrous
Acid Mutagenesis. Curr Microbiol. 2010
May 20. [Epub ahead of print] PubMed
PMID: 20490495.
Berge C, Froloff N, Kalathur RK, Maumy
M, Poch O, Raffelsberger W, Wicker
N (2010) Multidimensional fitting for
multivariate data analysis. J Comput Biol
17: 723-32
Bich C, Bovet C, Rochel N, Peluso-Iltis C,
Panagiotidis A, Nazabal A, Moras D, Zenobi
R (2010) Detection of nucleic acid-nuclear
hormone receptor complexes with mass
spectrometry. J Am Soc Mass Spectrom
21: 635-45
Bieniossek C, Nie Y, Frey D, Olieric
N, Schaffitzel C, Collinson I, Romier
C, Berger P, Richmond TJ, Steinmetz
MO, Berger I. Automated unrestricted
multigenerecombineering for multiprotein
complex production. Nat Methods. 2009
Jun;6(6):447-50.
Bonnet J., Wang Y-H., Spedale G., Atkinson
R.A., Romier C., Hamiche A., Pijnappel
W.W.M. P., Timmers H.Th. M., Tora L.,
Devys D. and Kieffer B. (2010) Structural
plasticity of SCA7 domains defines their
differential nucleosome binding properties.
EMBO Reports, In press.
Börjesson A, Lagerquist M, Liu C, Shao R,
Windahl S, Karlsson C, Sjögren K, Movérare-Skrtic S, Antal M, Krust A, Mohan S,
Chambon P, Sävendahl L, Ohlsson C. The
role of estrogen receptor-alpha in growth
plate cartilage for longitudinal bone growth.
J Bone Miner Res. 2010 Jun 18.
Costello P, Nicolas R, Willoughby J, Wasylyk B, Nordheim A, Treisman R. J Immunol.
2010 Jun 16. [Epub ahead of print]PMID:
20554967 [PubMed - as supplied by
Publisher] Ternary Complex Factors SAP-1
and Elk-1, but Not Net, Are Functionally
Equivalent in Thymocyte Development.
Bossenmeyer-Pourie, C., S. Blaise, G. Pourie, C.Tomasetto, S. Audonnet, S. Ortiou, V.
Koziel, M. C. Rio, J. L. Daval, J. L. Gueant,
and B. Beck, 2010, Methyl donor deficiency
affects fetal programming of gastric ghrelin
cell organization and function in the rat: Am
J Pathol, v. 176, p. 270-7.
Cronin T, Raffelsberger W, Lee-Rivera I,
Jaillard C, Niepon ML, Kinzel B, Clerin E,
Petrosian A, Picaud S, Poch O, Sahel JA,
Leveillard T (2010) The disruption of the
rod-derived cone viability gene leads to
photoreceptor dysfunction and susceptibility to oxidative stress. Cell Death Differ
17: 1199-210
Boumlic A, Nomine Y, Charbonnier S,
Dalagiorgou G, Vassilaki N, Kieffer B, Trave
G, Mavromara P, Orfanoudakis G (2010)
Prevalence of intrinsic disorder in the
hepatitis C virus ARFP/Core+1/S protein.
Febs J 277: 774-89
Brasse D, Mathelin C, Leroux K, Chenard
MP, Blaise S, Stoll I, Tomasetto C, Rio
MC. Matrix metalloproteinase 11/stromelysin-3 exerts both activator and repressor
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Budin, G., M. M. Dimala, V. Lamour, P.
Oudet, C. Mioskowski, S. Meunier, L.
Brino, and A. Wagner, 2010, A chemical
labeling strategy for proteomics under
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Cammas L, Trensz F, Jellali A, Ghyselinck
NB, Roux MJ, Dolle P (2010) Retinoic
acid receptor (RAR)-alpha is not critically
required for mediating retinoic acid effects
in the developing mouse retina. Invest
Ophthalmol Vis Sci 51: 3281-90
Calippe B, Douin-Echinard V, Delpy L,
Laffargue M, Lélu K, Krust A, Pipy B,
Bayard F, Arnal JF, Guéry JC, Gourdy P.
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Canto C, Jiang LQ, Deshmukh AS,
Mataki C, Coste A, Lagouge M, Zierath
JR, Auwerx J (2010) Interdependence of
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Cell Metab 11: 213-9
Charlot C, Dubois-Pot-Schneider H,
Serchov T, Tourrette, Y, Wasylyk B. Posttranslational modifications and sub-cellular
localization of Ets transcription factors:
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Cheng L, Guo J, Sun L, Fu J, Barnes PF,
Metzger D, Chambon P, Oshima RG,
Amagai T, Su DM (2010) Postnatal Tissuespecific Disruption of Transcription Factor
FoxN1 Triggers Acute Thymic Atrophy. J Biol
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125
NOTES
Notes
127
where we are
olm
eC
te
d
rou
Highway exit N°5
Illkirch-Nord
Baggersee
ar
A35
PARIS
NANCY
METZ
STRASBOURG
STRASBOURG
CITY CENTER
Tram A
Direction Illkirch
Lixenbuhl
Hy
p
erm
ark
et
N
Direction
Parc d’Innovation
N
NW
NE
E
W
E
S
SW
d Kast
Alfre
Faculté de
Pharmacie
ler
MULHOUSE
COLMAR
Aéroport
Strabourg-Enztheim
Highway exit N°5
Illkirch-Graffenstaden
Strasbourg-Meinau
S
Rue
A35
SE
O
Tram A
Station
Campus Illkirch
Tram A
Direction Hautepierre
Maillon
Pôle API
Bld
Sé
Bra bastien
ndt
Parc d’Innovation
From Strasbourg airport (Entzheim):
Take the shuttle (train, TER every 15 mins) that stops at
the Strasbourg railway station: Journey time is 10 minutes.
From Strasbourg railway station:
Underground trams leave every 5 minutes. Take Tram A
(direction Illkirch Lixenbuhl). Alight at the stop Campus
d’Illkirch. Journey time is 25 minutes.
From the Tram station Campus d’Illkirch:
Take the Bus 63 (direction Plobsheim Rhin) and alight
at the stop Parc d’Innovation. Follow Boulevard Sebastien
Brant. At the roundabout, follow the second exit, Boulevard Gonthier d’Andernach and turn left on to Rue Laurent Fries. The IGBMC will be on your right.
Or walking:
Cross the tracks and passing by the Velo Parc, continue
on to the roundabout. Take Boulevard Sebastien Brant
(third exit). At the second roundabout take the first exit,
Boulevard Gonthier d’Andernach and turn left in to Rue
Laurent Fries. The IGBMC will be on your right.
By car:
Take the 5th Highway exit and then follow the direction
Parc d’innovation. At the first roundabout take the fourth
exit, Boulevard Sebastien Brant, then at the second take
the second exit and turn left in to Rue Laurent Fries. The
IGBMC will be on your right.
© Copyright 2010
Produced by:
IGBMC
Texts: IGBMC Teams, Technical Platforms,
Core Facilities, Students & Post-docs Board
Print:
Valblor
Conception, Design, and Layout:
Office of Communication IGBMC,
Photography:
Lola Velasquez, Patrice Latron,
Office of Communication IGBMC
A big thank you goes out to all !
Institut de Génétique et de Biologie Moléculaire et Cellulaire
1 rue Laurent Fries / 67404 Illkirch CEDEX / France
igbmc@igbmc.fr