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Associated laboratories : IGBMC (Strasbourg)


• RNA diseases
We are studying the function of non-coding RNA and their implication in human genetic diseases. Our team focuses on two main subjects. First, we are studying the regulation of the biogenesis of microRNA by specific RNA binding proteins in various cancer cells and genetic diseases. Next, we are studying the implication of long non-coding RNA in human diseases. Indeed, it is now clear that most of our genome is transcribed, but that only a small portion is associated with protein coding gene. Furthermore, it has been recently demonstrated that these long non-coding RNA can be pathogenic, especially when containing large expansion of tri-, tetra-, penta- or hexa-nucleotide repeats. These RNA gain-of-function diseases include the most common muscular dystrophies in adults, the Myotonic Dystrophies (DM1 and DM2, caused by hundred to thousand CUG and CCUG RNA repeats, respectively), the neurodegenerative Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS, caused by 50 to 200 CGG repeats), the recently identified and most common genetic cause of Amyotrophic Lateral Sclerosis associated to Frontotemporal Dementia (chromosome 9ALS-FTD, which is caused by hundred of CCGGGG repeats) and the rare, but deleterious, Spinocerebellar Ataxia 10, 31 and 36 (SCA10 : AUUCU repeats, SCA31 : UGGAA repeats and SC36 : CCUGGG repeats).
In myotonic dystrophies, the expanded CUG or CCUG RNA repeats accumulate in pathogenic nuclear RNA aggregates that sequester a specific RNA binding protein, Muscleblind like 1 (MBNL1), leading to MBNL1 depletion, molecular changes and ultimately in the pathological symptoms. Importantly, a similar model is proposed for all other RNA gain-of-function diseases, however the identities of the sequestered proteins are, yet, unclear. Thus, very little is yet known on the proteins sequestered and the molecular mechanisms involved in FXTAS, SCA10, SCA31, SCA36 and ALS-FTD. Our goal is to elucidate the molecular causes of these disorders. We are particularly focusing on the RNA binding proteins sequestered by these repeats and the cellular and physiological consequences of such sequestration.
Contact : Nicolas Charlet

• Biocomputing
Thème de recherche : Etude des bases moléculaires de l’affinité et de la spécifité de la reconnaissance macromoléculaire par des méthodes de simulation numérique. Quantification de l’affinité d’assemblages protéine-protéine et protéine-peptides et identification des acides aminés qui jouent un rôle particulier dans l’affinité et la sélectivité de l’assemblage. Applications au développement de molécules interférant avec la reconnaissance et contribution à l‘étude des bases moléculaires des circuits de régulation cellulaires.
Contact : Annick Dejaegere

• Molecular and cellular mechanisms of neural development
>Research theme : Transcription factors and cell differentiation in vivo. Molecular mechanisms of neural development, with a particular emphasis on glial cells and microglia. Drosophila glia cells behave like microglia, the resident macrophages of the vertebrate nervous system. These two cell populations share a recently identified developmental pathway and play a key role in reshaping the nervous system during development, inflammation, injury and degeneration.
>Real time analyses of collective migration in the nervous system.
>Model : Animal models, Drosophila and mouse, for in vivo analyses. Cell cultures for in vitro analyses.
>Approaches : Molecular and cell biology. Genetics, Imaging. Genetic and molecular screens.
Contact : Angela Giangrande

• Physiopathology of neuromuscular diseases
>Thematics : Skeletal muscles represent nearly half of the dried body weight, are composed of multinucleated cells that can reach several centimeters, and are essential for movement, thermogenesis and metabolic homeostasis. More than 100 genes are linked to muscle defects, leading to different classes of myopathies. Moreover, muscle weakness and sarcopenia are associated with other common diseases and physiological aging.
Our team study the impact of proteins regulating the intracellular organization of skeletal muscle and mutated in congenital myopathies. The regulation of normal muscle fibers organization and the pathological mechanisms are not well understood.
Our main focus is on identifying the genetic causes of several severe congenital myopathies with high throughput sequencing, linking these genes into common pathways, characterizing faithful animal models, and using systemic approaches to build an overview of the normal and diseased muscle. In addition, we validate therapeutic rescues in our models as pre-clinical proof-of-concept.
>Approaches : Human genetics and high throughput sequencing, imaging in cells and in vivo imaging in animals, physiopathology in animal models (zebrafish, mice), gene transfer with viral vectors and pre-clinical trials.
Contact : Jocelyn Laporte

• Morphogenèse épithéliale chez C. elegans
. Thème de recherche : Nature des mécanismes qui contribuent aux changements de forme des cellules épithéliales pendant la morphogenèse épithéliale (rôle du cytosquelette, du trafic membranaire, des jonctions, nature des forces exercées). Processus permettant de coordonner les changements de formes entre tissus adhésifs (phénomènes de mécano-transduction).
. Matériel biologique utilisé : nématode C. elegans.
. Approches : cribles génétiques, imagerie dynamique, biologie cellulaire, modélisation. Dans le cadre d’un projet soutenu par l’ERC qui a pour objectifs généraux de définir le rôle des forces mécaniques dans la morphogenèse d’un embryon, une des priorités sera de mesurer les valeurs relatives des forces mécaniques selon les principaux axes de l’embryon à l’aide de sonde fluoresencetes et d’expérience d’ablation.
Contact : Michel Labouesse

• Pathophysiological function of nuclear receptor signaling
With the mouse as a mammalian model, and making an extensive use of site-directed cell-specific temporally-controlled somatic mutagenesis and transgenesis, our projects are aimed at 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.
For instance, anabolic and catabolic pathways controlled by androgens and glucocorticoids in skeletal muscle under various phathophysiological conditions (exercise, fasting) will be characterized at the molecular level by chromatin immunoprecipitation of the androgen and glucocorticoid receptors (ChIP seq) and by RNA seq.
Contacts : Daniel Metzger, Pierre Chambon

• Bases moléculaires de la morphogenèse
Thèmes de recherche : Patterning et différentiation de l’axe musculo-squelettique chez les vertébrés. Analyse génomique (microarrays, bioinformatique, proteomique, séquençage haut débit, ChIP seq et RNA seq) du développement du mésoderme paraxial in vivo et ex-vivo (cellules souches embryonnaires). Imagerie haute-résolution des mouvements cellulaires au cours de la formation de l’axe embryonnaire. Biologie quantitative (Systems Biology) appliquée a l’étude du développement embryonnaire. Systèmes modèles utilises : zebrafish, poulet, serpent, souris et études cliniques.
Contact : Olivier Pourquié

• Physiopathologie des ataxies récessives
Thèmes de recherche : Bases moléculaires et mécanismes physiopathologiques des ataxies récessives, un groupe hétérogène de pathologies neurodégénératives présentant une atteinte cérébelleuse et/ou spinocérébelleuse. Caractérisation de la voie de biosynthèse de noyaux fer-souffre, cofacteurs essentiels impliqués dans plusieurs pathologies humaines. Combinaison d’approches : génétique, biologie moléculaire, biochimie (enzymatiques et études de complexes protéiques), biologie cellulaire (cellules souches, différentiation neuronale, imagerie), développement et caractérisation de modèles animaux et cellulaires.
Contact : Hélène Puccio

• Networks and protein complexes regulating eukaryotic mRNA decay
Themes : Analysis of the post-transcriptionnal control of gene expression through messenger RNA degradation. If for several years numerous studies focused on the regulation of gene expression by transcription, it has recently become clear that a wide extent of the regulation of gene expression results from post-transcriptionnal regulatory events targeting two related processes : translation and mRNA decay. Our work uses a combination of experimental approaches (RNA studies, transcriptomic, analyses of protein interaction, proteomic, protein complex purification (Method TAP), recombinant proteins, post-translationnal protein modifications, structural analyses, biochemistry, genetics, in vivo analyses, cellular biology strategies) to study the degradation of mRNAs. An important fraction of our work concentrates on the analysis of protein-protein interactions, protein complexes and of their post-translationnal modifications. Our work analyzes in parallel yeast and human cells. The physiological and pathological consequences of alteration of mRNA decay are also at the heart of our interests.
Contact : Bertrand Séraphin

• Transcriptional networks and their regulation during cell differentiation
Research program : One of the most appealing questions regarding transcription regulation in eukaryotes is to understand how activators convey their message to the basal transcription machinery in the chromatin context characterized by an extreme DNA compaction. Another key question is to identify transcriptional networks that maintain the pluripotency of embryonic stem cells and to understand their regulation during cell differentiation. We are using a combination of genomic approaches (transcriptomic, high-throughput sequencing : ChIP-seq, RNA-seq), proteomic analyses (including complex purification and biochemistry), genetics and cellular biology (High resolution imaging) to address these fundamental questions.
Contact : Laszlo Tora

• Mécanique des fluides et cardiogénèse
Thèmes de recherche : Explorer le rôle des forces de friction générées par le flux sanguin lors du développement du système cardiovasculaire. Explorer le rôle des forces hydrodynamiques générées par les cils moteurs. Identification des voies de signalisation et de nouveaux gènes dont l’activité est regulée par les forces mécaniques associés aux battements cardiaque. Caractérisation des principes hydrodynamiques impliquées dans les processus de morphogénèse. Techniques avancées d’imagerie in vivo, de biologie cellulaire et approches de génétique et de biologie moléculaire. Animal modèle : poisson zèbre (Danio rerio).
Contact : Julien Vermot