Epigenetics and Soma

Research Interests

We are interested in expanding studies which have been classically associated with the antigen receptor (immunoglobulin) genes of B lymphocytes: random mono-allelic expression and DNA modification reactions, namely, somatic hypermutation (SHM) and class switch recombination (CSR).

Random mono-allelic expression is the most striking example of an epigenetic phenomenon, because at the level of each cell only one of two identical molecules (the alleles) is expressed. It ensures that each B cell expresses only one antibody but it occurs also in other loci and cell types. We are studying the immunoglobulin genes as a model to dissect early epigenetic mechanisms that determine which allele is going to be expressed. We are also designing screens using model organisms and cell lines to identify additional regions in the genome undergoing random mono-allelic expression.

In SHM, point mutations are introduced into the variable region of the Ig heavy and light chain genes in germinal center activated B cells, generating the required diversity to fuel the affinity maturation of antibodies, a phenomenon that re-enacts the evolutionary process. In contrast, CSR is a deletional DNA recombination reaction that combines the variable region of the antibody with different constant regions, each with unique effector functions. Activation-Induced Deaminase (AID) plays a pivotal role in adaptive immunity because it is essential for SHM and CSR. However, its mutagenic ability has a pernicious side effect and AID has been implicated in B lymphomas and other neoplasias. Finally, because AID belongs to a family of cytidine deaminases including members with anti-retroviral properties due to their targeting of viral cDNA, cytidine deamination of DNA is yet another unforeseen link between innate and adaptive immunity. We plan to use classical molecular approaches and genetically engineered mice to discover AID co-factors for CSR, to address the rules governing AID targeting to the immunoglobulin loci and to establish murine models to evaluate the impact of ectopic expression of AID. In addition, we are interested in cloning molecules from distant species able to introduce lesions in DNA, with the goal of better elucidating the evolution of somatic DNA modification reactions.

Group Members

Research Project

AID and beyond

Funding

Marie Curie International Reintegration Grants (IRG) (submitted)
AID and beyond

Publications

McBride, KM, Gazumyan, A, Woo, EM, Barreto, VM, Robbiani, DF, Chait, BT, Nussenzweig, MC. (2006). Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation Proc Natl Acad Sci U S A. 6;103(23) :8798-803

Barreto VM, Pan-Hammarstrom Q, Zhao Y, Hammarstrom L, Misulovin Z, Nussenzweig (2005). AID from bony fish catalyzes class switch recombination Journal of Experimental Medicine 202(6) :733-8

Barreto V., Ramiro A., Nussenzweig, M.C. (2005). Activation-induced deaminase: controversies and open questions. Trends Immunol 26(2) :90-6

Yannoutsos, N., Barreto, V., Misulovin, Z., Gazumyan, A., Yu, W., Rajewsky, N., Peixoto, B.R.,Eisenreich, T. and Nussenzeig, M.C. (2004). A cis element in the recombinase activating gene locus regulates gene expression by counteracting a distant silencer. Nature Immunology 5(4) :443-50

McBride KM, Barreto V, Ramiro AR, Stavropoulos P, Nussenzweig MC. (2004). Somatic Hypermutation Is Limited by CRM1-dependent Nuclear Export of Activation-induced Deaminase Journal of Experimental Medicine 199(9) :1235-44

Barreto, V, Reina-San-Martin, B., Ramiro, A. R., McBride, K. M., and Nussenzweig, M. C. (2003). C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Molecular Cell 12 :501-508

Barreto, V., Marques, R., and Demengeot, J. (2001). Early death and severe lymphopenia caused by ubiquitous expression of the Rag1 and Rag2 genes in mice European Journal of Immunology 31 :3763-3772

Barreto, V., Meo, T. and Cumano, A. (2001). Mice tri-allelic for the IgH locus: implications for VHDJH recombination Journal of Immunology 166 :5638-5645

Barreto, V. and Cumano, A. (2000). Frequency and characterization of phenotypic Ig heavy chain allelically included IgM-expressing B cells in mice. Journal of Immunology 164 :893-9