Osipovich Oleg, Milley Robin, Meade Amber, Tachibana Makoto, Shinkai Yoichi, Krangel Michael S, Oltz Eugene M
Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
Nat Immunol. 2004 Mar;5(3):309-16. doi: 10.1038/ni1042. Epub 2004 Feb 22.
The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.
通过V(D)J重组进行的抗原受体基因的组织和阶段特异性组装,受靶基因片段染色质可及性变化的调控。这种动态重塑过程由顺式作用启动子和增强子协调,它们作为可及性控制元件发挥作用。激活或抑制染色质对V(D)J重组酶可及性的基本表观遗传机制仍不清楚。我们现在证明,一种组蛋白甲基转移酶会凌驾于可及性控制元件功能之上,并削弱染色体基因片段的V(D)J重组。募集的组蛋白甲基转移酶会在局部染色质环境中引发广泛改变,包括组蛋白修饰的改变和DNA的从头甲基化。这些发现表明,组蛋白甲基转移酶在淋巴细胞发育过程中对抗原受体基因组装的组织和阶段特异性抑制中起关键作用。