Control of B Cell Development by Histone Methylation

组蛋白甲基化控制 B 细胞发育

• 批准号: 7112522
• 负责人: LANCE R THOMAS
• 金额: $ 4.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112522
• 关键词: antigen receptors; chromatin; epigenetics; gene expression; genes; histones; lymphocyte; methylation; model; role

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.

描述（由申请人提供）：为了产生介导哺乳动物免疫的抗原受体库，淋巴细胞必须通过V(D)J重组从不同的编码段组装免疫球蛋白基因。靶向重组机制必须严格调控，因为畸变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进入。组蛋白3 （H3-K9）上赖氨酸9的甲基化修饰与不可接近的染色质和转录抑制状态有关。我们已经证明，H3-K9组蛋白甲基转移酶G9a削弱了V(D)J重组酶的可及性。我们假设G9a介导的H3-K9甲基化控制了B淋巴细胞体内发育的多个方面，包括抗原受体基因的有序重排。为了验证这一假设，我们建立了一个含有G9a基因条件空等位基因的小鼠模型，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细胞中调控B细胞成熟、抗原受体基因组装和效应功能中的作用。