Mouse Molecular Genetics - CNRS URA2578  


  HEADAVNER Philip Prof. / philip.avner@pasteur.fr
  MEMBERSPermanent Members : Dr. CLERC Philippe / Dr. ROGNER Ute / Dr. ROUGEULLE Claire Temporary Members : ATTIA Mikaël / DUFFIÉ Rachel / Dr. HE Chenxia / Dr. MOREY Céline / Dr. NAVARRO Pablo / OLDFIELD Andrew 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 different 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.

Recent major advances in our research on X-inactivation have concerned particularly the way in which the onset of X-inactivation is tightly linked to, and controlled by the onset of specific steps in the developmental process. Transcription of Xist, a non-coding RNA key to the X-inactivation process, was shown in the laboratory to be under the direct control of factors such as Nanog, Sox2 and Oct3/4 which are themselves key factors in maintaining cells of the early embryo in the undifferentiated pluripotential stem cell state. By identifying this direct regulatory link between X-inactivation initiation and pluripotency factor binding to regulatory sites within theXist gene, our findings provide a mechanistic underpinning for observations made concerning both nuclear programming and IPS cells (induced pluripotent cells). Other ongoing studies are analyzing different aspects of imprinted X-inactivation as it occurs in cells of the extra-embryonic lineages.

Current studies on Nap1l2, including two hybrid studies, have allowed us to define novel and unexpected interactions between Nap1l2 and other chromatin effectors. Structural studies aimed at clarifying the basis for these interactions are underway in collaboration with the group of Paul Freemont (Imperial College, London, UK).

Our studies on the genetics of diabetes have been centred around a functional analysis of the Arntl2 circadian rhythm gene which has been defined as a primary candidate for Idd6 associated diabetes resistance. Ongoing research is seeking to establish eventual links between Arntl2 and innate immunity mechanisms evolving Tlr1 which have been implicated as downstream components of Idd6 associated diabetes resistance.

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

Gmm.jpg

RNA-immuno-FISH using an antibody against Nanog (red) and a Xist probe (green) in female ES cells differentiated for 4 days. This picture shows that X chromosome inactivation identified by the presence of a Xist RNA domain on the inactive X chromosome is induced only in cells, which have lost the pluripotency marker Nanog (Navarro et al., Science, 2008).



  Publications

Navarro P, Chambers I, Karwacki-Neisius V, Chureau C, Morey C, Rougeulle C, Avner P (2008) Molecular coupling of Xist regulation and pluripotency. Science 321, 1693-1695.

Attia M, Rachez C, De Pauw A, Avner P and Rogner UC. (2007) Nap1l2 promotes histone acetylation activity during neuronal differentiation. Mol. Cell. Biol. 27, 6093-6102.

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.

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.

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.



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Activity Reports 2009 - Institut Pasteur
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