Bernard Binétruy Molecular mechanisms of differentiation of Embryonic Stem Cells
Course and current status
1980: Master in biochemistry and physiology at the University of Nice.
1981-1988: PhD student (1981-1982), then INSERM researcher (1983-1988) at the Centre de Biochimie, Nice (scientifc director Dr F. Cuzin). My research was focused on the oncogenic properties of the Bovine Papilloma Virus type1 (BPV1) in rat embryo fibroblasts.Publications in : Nature, EMBO J., Virology, PNAS and Oncogene.
oct.1982: Thèse de 3ème cycle and Nov. 1988: Thèse de doctorat d'état in microbiology, University of Nice.
déc.1988-june1991: post-doc fellow in the laboratory of Dr M. Karin, department of pharmacology, School of medicine, UCSD, La Jolla, USA. Fellowship of the Fogarty International Center. During my stay in San Diego I showed that the Ras oncogene augments cJun activity and stimulates phosphorylation of its activation domain and that oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of cJun on serines 63 and 73. This work led to the identification and the characterisation, two years later, by the laboratory of M. Karin of the JNK signal transduction pathway. Publications in: two in Nature (one « full paper ») and two in Mol. Cell. Biol.
june 1991-september 1999: back in France, I started my own lab in Paris area in the Cancer Research Institute, CNRS, Villejuif. We developed a differential screening of a cDNA library to identify and then characterize c-Jun target genes. Publications in : EMBO J., Mol. Cell. Biol., Oncogene and Cell Growth & Diff. october 1995: Research Director at Inserm.
sept. 1999 to august 2005: I moved to Nice, Inserm U568 laboratory, Faculté de Médecine, Nice. In this new laboratory, I started a new research program focused on the analysis of the molecular mechanisms involved in the differentiation of mouse ES cells. Publications in : Oncogene, Biochem. J., CMLS, Diabetes and Stem Cells.
Since sept. 2005 I moved to Marseille, Inserm UMR626 laboratory, Faculté de Médecine Timone, Marseille. In this lab, I continue my research on the differentiation of ES cells. Publications in : Stem Cells and Stem Cells and Development.
From 01-01-2008 : I am the Director of the Institut de Physiopathologie Humaine de Marseille, IFR 125.
Scientific summary
Our project consists, first, to isolate and analyze iPSC lines from patient suffering from Facio-Scapulo-Humeral muscular Dystrophy (FSHD), a common autosomal dominant neuromuscular disorder; and secondly to screen these cells with a chemical library for potential therapeutic molecules. In this pathology the locus was mapped to a 3.3 kb repeated subtelomeric region of chromosome 4. In the general population, the number of repeats varies between 11 and 150 units, whereas FSHD patients carry fewer than 11. Intriguingly, there is no FSHD candidate gene clearly identified so far. Numerous works indicate that FSHD is not the result of a classical mutation within a coding sequence but rather related to chromatin organization and epigenetic alteration. Search for pharmacological therapies has been hampered by the poor in vitro proliferative capacity of isolated muscle cells and, consequently, the lack of experimental model reproducing cellular muscle dysfunctions. Moreover, in the case of FSHD, no animal model is available.
Introduction of a defined set of transcription factors in human somatic cells lead to the establishment of induced pluripotent stem cells (iPSCs) that have been reprogrammed to an embryonic-like pluripotent state. In addition to their potential use as the starting material for differentiated cells in regenerative medicine, patient-derived iPSCs can be created to examine the disease process at a cellular level and to test responses to possible drugs. Therefore, establishment of iPSC lines from FSHD patients will allow the analysis of this pathology at the cellular and molecular levels. Furthermore, the strategy proposed here presents a major interest in the understanding of epigenetic changes associated with the reprogramming of repetitive DNA sequences during differentiation in normal cells and pathologies involving epigenetic alterations.
Our specific aims are: i) the analysis of the epigenetic regulations at the FHSD locus in patient-derived versus control iPSCs before and after differentiation; ii) to look for therapeutic molecules by screening a chemical library with the epigenetic of FSHD as readout.
