Control of B Cell Development by Histone Methylation

描述(申请人提供)：为了产生介导哺乳动物免疫的抗原受体谱系，淋巴细胞必须通过V(D)J重组从不同的编码片段组装免疫球蛋白基因。针对重组机制的靶向必须受到严格的监管，因为异常会导致与白血病和淋巴瘤相关的染色体易位。目前的模型表明，组蛋白尾部的修饰控制着染色质结构和重组机制的通达。一种修饰，组蛋白3(H3-K9)上赖氨酸9的甲基化与染色质不可及和转录抑制状态有关。我们已经证明，G9a，一种H3-K9组蛋白甲基转移酶，削弱了V(D)J重组酶的可及性。我们假设G9a的H3-K9甲基化控制体内B淋巴细胞发育的多个方面，包括抗原受体基因的有序重排。为了验证这一假设，我们建立了一个小鼠模型，该模型含有G9a基因的条件零等位基因，我们将在B细胞发育的特定阶段删除该等位基因。这些实验将揭示G9a在成熟B细胞中调节B细胞成熟、抗原受体基因组装和效应器功能中的作用。

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.