Chercheur non statutaire
The general aim of the team is the understanding of the generation of the repertoire of antigen receptors in lymphocytes in order to promote the diversity of the immune system while minimizing the risks of genomic instability that could lead to cancers. In particular, we are focusing on the functional role of epigenetic mechanisms and 3D organization of the nucleus in the regulation of V(D)J recombination of antigen-receptor loci.
The general interest of the team is to investigate the functional role of chromosome conformation, chromatin environment and nuclear organization in the regulation of V(D)J recombination during lymphocyte development. The tight regulation of V(D)J recombination is crucial to find the right balance between the generation of millions of double-stranded breaks in millions of B and T cells each day to create the vast repertoire of antigen-receptors, on the one hand, and the maintenance of genome stability to avoid risks of translocations, mutations, deletions that could lead to leukemia or lymphomas.
We are using a unique combination of live and fixed single cell analyses (immunofluorescene, RNA and DNA FISH, live cell imaging) as well as genome-wide approaches (3C-technology, RNA/ChIP-seq) to investigate:
(1) the functional impact of chromatin and nuclear environment on antigen receptor loci expression and recombination,
(2) the links between 3D locus conformation, cis/trans genomic interactions, and regulation of recombination.
This should provide new insights into the role of chromatin and nuclear dynamics in the regulation of gene expression, DNA recombination, preservation of genome integrity and the origins of lymphoid-related diseases.
Keywords: Epigenetics, nuclear organization, V(D)J recombination, lymphocyte development, antigen-receptor locus.
Chaumeil J., Micsinai M., Ntziachristos P., Roth D.B., Aifantis I., Kluger Y., Deriano L. and Skok J.A. (2013) The RAG2 C-terminus and ATM control RAG activity to limit the number of potential translocation substrates. Nature Comm 31;4 : 2231
Chaumeil J., Micsinai M., Ntziachristos P., Deriano L., Wang J.M.H., Ji Y., Nora E., Rodesch M.J., Jeddeloh J.A., Kluger Y., Aifantis I., Schatz D.G. and Skok J.A (2013) Higher-order looping and nuclear organization of antigen receptor loci facilitates targeted RAG cleavage and regulated rearrangement in recombination centers. Cell Reports 3(2) : 359-37.
Deriano L., Chaumeil J., Coussens M., Multani A., Chou Y.F., Alekseyenko A.V., Chang S., Skok J.A. and Roth D.B. (2011) The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 471(7336) : 119-23
Chaumeil J., Le Baccon P., Wutz A. and Heard E. (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20(16) : 2223-37