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 especially, 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.

Recent advances in our research on X-inactivation have concerned the initiation step when X-inactivation is put in place concomitantly with the onset of differentiation. We showed last year that the transcription of Xist, a large non-coding RNA critical to the onset of X-inactivation, is directly controlled by the pluripotency factors Oct3/4, Nanog and Sox 2. In a recent Nature publication, we demonstrated that the Tsix non-coding RNA, which is an Xist antisense RNA which participates in the regulation of Xist is also under the direct control of a series of other pluripotency factors which include Klf4 and c-myc. Intriguingly, therefore the regulatory circuits linking the onset of X-inactivation initiation with differentiation, depend on the four pluripotency factors, cmyc, Oct3/4, Nanog and Klf4 that Yamanaka and his colleagues have shown to be sufficient to reprogram somatic cells to the pluripotent state. Studies are ongoing to establish the role of other members of the pluripotency network in controlling the X-inactivation process.

Other studies on X-inactivation have been centred around the analysis of the X-controlling element or Xce locus which influences the choice of X-chromosome to inactive, and differences in the X-inactivation process in different cell lineages. Using Trophoblastic Stem (TS) and XEN (Extra Embryonic Endoderm) cell lines representing two closely related extra-embryonic cell lineages we have shown that the inactive X in TS cells conserves, for example, a plasticity manifested by its capacity to be partially or totally reactivated, which is totally absent from XEN cells, and in all probability, is linked to the need of some cells in the early embryo to undergo a X chromosome reactivation-inactivation cycle at the blastocyst stage. The partial reactivation of the X chromosome was shown to preferentially affect regions of the X-chromosome lacking the major repressive epigenetic histone marks.

Our studies on the nervous tissue specific nucleosomal assembly protein (Nap1L2) have revealed that this protein is not only capable of forming homodimers with itself but also heterodimers with other members of the Nap family of proteins. Our results based on double hybrid, biochemical and genetic analyses, strongly suggest that the capacity of Nap family members to form heterodimers with each other plays an important role in determining the activity and probably the specificity of these factors in chromatin assembly and other related activities. Ongoing analysis extend these studies of the interactions of Nap1l2 beyond the Nap family itself to a series of other interactors defined by two hybrid and mass spectroscopy studies.

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

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. PMID: 17591696

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. PMID: 18802003

Maenner S, Blaud M, Fouillen L, Savoye A, Marchand V, Dubois A, Sanglier-Cianférani S, Van Dorsselaer A, Clerc P, Avner P, Visvikis A and Branlant C (2009) 2D structure of the A region of Xist RNA and its implication for PRC2 association, PLoS Biology 8(1), e1000276.

Navarro P, Oldfield A, Legoupi J, Festuccia N, Dubois A, Attia M, Schoorlemmer J, Rougeulle C, Chambers I and Avner P (2010) Molecular coupling of Tsix regulation and pluripotency. Nature 468, 457-460 PMID: 21085182

He C, Prevot N, Boitard C, Avner P, Rogner UC. (2010) Inhibition of type-1 diabetes by upregulation of the circadian rhythm related Aryl hydrocarbon receptor nuclear translocator-like protein 2. Immunogenetics DOI : 10.1007/s00251-010-0467-7. PMID: 20676886