Control of B Cell Development by Histone Methylation

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DESCRIPTION (provided by applicant): To generate the antigen receptor repertoire that mediates mammalian immunity, lymphocytes must assemble immunoglobulin genes from separate coding segments via V(D)J recombination. Targeting of the recombination machinery must be tightly regulated because aberrations lead to chromosomal translocations associated with leukemia and lymphomas. Current models indicate that modifications of histone tails control chromatin structure and access of the recombination machinery. One modification, methylation of lysine 9 on histone 3 (H3-K9) is associated with inaccessible chromatin and a transcriptionally repressive state. We have shown that G9a, an H3-K9 histone methyltransferase, cripples accessibility to V(D)J recombinase. We hypothesize that H3-K9 methylation by G9a controls multiple aspects of B lymphocyte development in vivo, including the ordered rearrangement of antigen receptor genes. To test this hypothesis, we generated a mouse model harboring a conditional null allele of the G9a gene, which we will delete at specific stages of B cell development. These experiments will reveal the role of G9a in the regulation of B cell maturation, antigen receptor gene assembly, and effector functions in mature B cells.