Morgane Gauthier

Inserm

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Marc Peschanski

Inserm

Cécile Martinat

Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques

Yves Maury

Laboratoire Physiologie Cellulaire & Végétale

Geneviève Piétu

Association Française de Chirurgie

Jérôme Alexandre Denis

Inserm

Sophie Aubert

Airbus (India)

Rémi Vernet

Hôpital Paul-Brousse

Karine Giraud-Triboult

Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques

Antoine Marteyn

University of Geneva

Christine Baldeschi

Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques

Cooperative Institutions

Inserm

Centre National de la Recherche Scientifique

Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques

Université Paris Cité

Sorbonne Université

Institut Cochin

Association Francaise contre les Myopathies

Sorbonne Paris Cité

Université d'Évry Val-d'Essonne

Université Paris-Saclay

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MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-widecis-regulatory module analysis

Nucleic Acids Research (2016)

Marc Santolini Iori Sakakibara Morgane Gauthier Francesc Ribas‐Aulinas Hirotaka Takahashi

Myogenic regulatory factors of the MyoD family have the ability to reprogram differentiated cells toward a myogenic fate. In this study, we demonstrate that Six1 or Six4 are required for the reprogramming by MyoD of mouse embryonic fibroblasts (MEFs). Using microarray experiments, we found 761 genes under the control of both Six and MyoD. Using MyoD ChIPseq data and a genome-wide search for Six1/4 MEF3 binding sites, we found significant co-localization of binding sites for MyoD and Six proteins on over a thousand mouse genomic DNA regions. The combination of both datasets yielded 82 genes which are synergistically activated by Six and MyoD, with 96 associated MyoD+MEF3 putative cis-regulatory modules (CRMs). Fourteen out of 19 of the CRMs that we tested demonstrated in Luciferase assays a synergistic action also observed for their cognate gene. We searched putative binding sites on these CRMs using available databases and de novo search of conserved motifs and demonstrated that the Six/MyoD synergistic activation takes place in a feedforward way. It involves the recruitment of these two families of transcription factors to their targets, together with partner transcription factors, encoded by genes that are themselves activated by Six and MyoD, including Mef2, Pbx-Meis and EBF.

Reprogramming

MyoD Protein

PITX2

10.1093/nar/gkw512

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Citations (31)

Human pluripotent stem cells for disease modelling and drug screening

BioEssays (2011)

Yves Maury Morgane Gauthier Marc Peschanski Cécile Martinat

Abstract Considerable hope surrounds the use of disease‐specific pluripotent stem cells to generate models of human disease allowing exploration of pathological mechanisms and search for new treatments. Disease‐specific human embryonic stem cells were the first to provide a useful source for studying certain disease states. The recent demonstration that human somatic cells, derived from readily accessible tissue such as skin or blood, can be converted to embryonic‐like induced pluripotent stem cells (hiPSCs) has opened new perspectives for modelling and understanding a larger number of human pathologies. In this review, we examine the opportunities and challenges for the use of disease‐specific pluripotent stem cells in disease modelling and drug screening. Progress in these areas will substantially accelerate effective application of disease‐specific human pluripotent stem cells for drug screening.

Human disease

10.1002/bies.201100071

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Citations (58)

Les cellules souches pluripotentes humaines

médecine/sciences (2011)

Yves Maury Morgane Gauthier Marc Peschanski Cécile Martinat

10.1051/medsci/2011274023

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Citations (6)

Mutant Human Embryonic Stem Cells Reveal Neurite and Synapse Formation Defects in Type 1 Myotonic Dystrophy

Cell stem cell (2011)

Antoine Marteyn Yves Maury Morgane Gauthier Camille Lecuyer Rémi Vernet

Neurite

10.1016/j.stem.2011.02.004

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Citations (96)

Les cellules souches pluripotentes humaines

médecine/sciences (2011)

Yves Maury Morgane Gauthier Marc Peschanski Cécile Martinat

10.1051/medsci/2011274443

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Citations (0)

Etude des mécanismes moléculaires de la Dystrophie Myotonique de Type 1 à l'aide de cellules souches embryonnaires humaines porteuses de la mutation causale

Morgane Gauthier

Les cellules souches embryonnaires humaines (hESC) representent un nouvel outilbiologique au potentiel prometteur pour l’amelioration de la comprehension des mecanismes moleculaires et cellulaires impliques dans le developpement de maladies monogeniques. Cette application est dans un premier temps devenue possible grâce a l’utilisation de lignees de cellules souches embryonnaires humaines porteuses de mutation causale de pathologie, obtenues au cours d’un diagnostique pre-implantatoire. Mon travail de these s’est inscrit dans la validation de ce nouveau concept en utilisant des lignees de cellules souches embryonnaires humaines porteuses de la mutation causale de la Dystrophie Myotonique de type 1 (DM1). Ces cellules, ainsi que leurs progenies neurales et mesenchymateuses representent un modele pertinent pour l’etude des consequences physiopathologiques de la mutation DM1 dans la mesure ou elles reproduisent certaines caracteristiques moleculaires connues de la pathologie. Mon projet a eu pour objectif de caracteriser d’un point de vue moleculaire et physiopathologique deux nouvelles alterations geniques identifiees par transcriptome differentiel entre les cellules controles et DM1. Ainsi, ce travail nous a permis d’identifier un nouveau marqueur, le facteur de transcription ZNF37A, dont l’expression est diminuee en association avec la mutation DM1 et qui serait implique dans les defauts myogeniques caracterisant cette pathologie. Parallelement nous avons identifie un nouveau defaut d’epissage alternatif d’un gene implique dans la guidance axonale, l’EphA5 qui pourrait etre implique dans les defauts cognitifs des patients DM1.

Source

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A defective Krab-domain zinc-finger transcription factor contributes to altered myogenesis in myotonic dystrophy type 1

Human Molecular Genetics (2013)

Morgane Gauthier Antoine Marteyn Jérôme Alexandre Denis Michel Cailleret Karine Giraud-Triboult

Myotonic dystrophy type 1 (DM1) is an RNA-mediated disorder caused by a non-coding CTG repeat expansion that, in particular, provokes functional alteration of CUG-binding proteins. As a consequence, several genes with misregulated alternative splicing have been linked to clinical symptoms. In our search for additional molecular mechanisms that would trigger functional defects in DM1, we took advantage of mutant gene-carrying human embryonic stem cell lines to identify differentially expressed genes. Among the different genes found to be misregulated by DM1 mutation, one strongly downregulated gene encodes a transcription factor, ZNF37A. In this paper, we show that this defect in expression, which derives from a loss of RNA stability, is controlled by the RNA-binding protein, CUGBP1, and is associated with impaired myogenesis—a functional defect reminiscent of that observed in DM1. Loss of the ZNF37A protein results in changes in the expression of the subunit α1 of the receptor for the interleukin 13. This suggests that the pathological molecular mechanisms linking ZNF37A and myogenesis may involve the signaling pathway that is known to promote myoblast recruitment during development and regeneration.

10.1093/hmg/ddt373

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Citations (13)

mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

Journal of Cell Science (2013)

Jérôme Alexandre Denis Morgane Gauthier Latif Rachdi Sophie Aubert Karine Giraud-Triboult

Patients with Myotonic Dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among those are cognitive dysfunctions, the origin of which has remained elusive due in part to the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis as mutant gene-carriers, in order to differentiate cells along the neural lineage. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, a RNA-binding protein whose function is defective in DM1 patients, resulted in the mTOR signaling alteration whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects.

10.1242/jcs.116285

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Citations (40)

Human pluripotent stem cells for genetic disease modeling and drug screening

Regenerative Medicine (2011)

Morgane Gauthier Yves Maury Marc Peschanski Cécile Martinat

Considerable hope surrounds the use of disease-specific pluripotent stem cells, which can differentiate into any cell type, as starting materials to generate models of human disease that will allow exploration of pathological mechanisms and the search for new treatments. Disease-specific human embryonic stem cells have provided a useful source for studying certain disease states. However, reprogramming of human somatic cells that use readily accessible tissue, such as skin or blood, to generate embryonic-like induced pluripotent stem cells has opened new perspectives for modeling and understanding a larger number of human pathologies. Here, we examine the challenges in creating a disease model from human pluripotent stem cells, and describe their use to model both cell-autonomous and non-cell-autonomous mechanisms, the need for adequate control experiments and the genetic limitations of human induced pluripotent stem cells. Progress in these areas will substantially accelerate effective application of disease-specific human pluripotent stem cells for drug screening.

Reprogramming

10.2217/rme.11.46

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Citations (5)