Mouse Molecular Genetics - CNRS URA2578  


  HEADAVNER Philip Prof. / pavner@pasteur.fr
  MEMBERSPermanent Members : Dr. CLERC Philippe / Dr. ROGNER Ute / Dr. ROUGEULLE Claire
Temporary Members : ATTIA Mikaël / Dr. CHANTALAT Sophie / CHRÉTIEN Adèle / DUFFIÉ Rachel / Dr. HE Chenxia / MOLARO Antoine / Dr. MOREY Céline / Dr. NAVARRO Pablo / OLDFIELD Andrew / VIGNEAU Sébastien
Research engineer : CHUREAU-POMMIER Corinne
Other members : DUBOIS Agnès / OLLIVIER Edith / VERON Corinne


  Annual Report

Starting from its interests in mouse genetics, the Unit has contributed widely both to progress in our knowledge of mouse genomics to studies on complex trait genetics and multifactorial and multigenic inheritance through its studies on type 1 diabetes in the mouse and, through its studies on the process of X-inactivation, to our understanding of facets of epigenetics.

Present research activities of the Mouse Molecular Genetics Unit are organised around two principal themes. The first concerns the epigenetic mechanisms of cellular and transcriptional control. Our studies on X-inactivation and the Nap112 (Nucleosomal assembly protein) gene fall under this heading through the central importance of chromatin structure and modification to their action. The second research theme concerns the genetics of polygenic and multifactorial inheritance. The model that we have studied for over a dozen years now concerns the genetic predisposition of the NOD (Non-obese diabetic) mouse to develop Type 1 diabetes.

Major recent advances in our research on X-inactivation have concerned the demonstration that the Xist gene critical to eutherian X-inactivation is absent from methatherians such as marsupials in which X-inactivation also occurs and that the non-coding Xist has evolved, at least in part, from the Lnx3 protein coding gene. X-inactivation in marsupials is therefore Xist independent and may be a carry-over from the meiotic silencing of the X chromosome occurring in the male germline. This finding has major implications for our understanding of the evolutionary history and constraints acting on dosage compensation mechanisms in mammals. Potentially highly important aspects of X-inactivation have also been opened up both through our implication of the nonsense-mediated decay pathway in Xist regulation and processing, and by our studies on Xist regulation by the Tsix antisense which have shown this is occur in part by altering the structure of the chromatin surrounding the Xist promoter. These studies have demonstrated that Tsix is not the oft searched for developmental regulator of Xist expression and in so doing opened the way to ongoing studies to define this element. Current studies on Nap1l2 are aimed at defining the protein complexes that mediate its action in neural stem cells and neurons as well as the downstream target genes critical to its action. Our diabetes studies have been marked by the finding that the Arntl2 circadian rhythm gene is a candidate for the mouse type 1 diabetes locus, Idd6 and has led to intense functional studies to further define its role. Whilst, our studies have shown that, at least part of the resistance due to the Idd6 locus is mediated via a modulation of regulatory T cell activity, recent results, carried out in collaboration with the Boitard laboratory at Cochin, have implicated Tlr1 and innate immunity mechanisms as core components in the diabetes resistance of our mouse strains carrying the Idd6 locus.

Keywords: epigenetics, X-inactivation, mouse genetics, multigenic inheritance, genetics of type 1 diabetes,Nap1l2, Nucleosomal assembly protein

Gmm.jpg

The Xist domain (green) marks the inactive X chromosome in these differentiating ES cells.



  Publications

Vigneau, S., Augui , S., Navarro, P., Avner, P., and Clerc, P. (2006). An essencial role for the DXPas34 tandem repeat and Tsix transcription in the counting process of X-chromosome inactivation. Proc Natl Acad Sci U S A. 103, 7390-7395.

Duret L, Chureau C, Samain S, Weissenbach J, Avner P. (2006) The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653-1655.

Hung M-S, Avner P and Rogner UC. (2006). Identification of the transcription factor ARNTL2 as a candidate gene for the tye 1 diabetes locus IDD6. Human Molecular Genetics 15, 2732-2742.

Navarro P, Page D, Avner P and Rougeulle C. (2006) Tsix-mediated epigenetic switch of a CTCF-flanked region of the Xist promoter determines the Xist transcription program. Genes & Development 20, 2787-2792.



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Activity Reports 2007 - Institut Pasteur
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