Histone acetylation determines the developmentally regulated accessibility for T cell receptor γ gene recombination
Histone acetylation determines the developmentally regulated accessibility for T cell receptor γ gene recombination
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DOI：
10.1084/jem.193.7.873
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发表时间：
2001-04-02
影响因子：
15.3
通讯作者：
Shimizu, A
中科院分区：
文献类型：
--
作者：
Agata, Y;Katakai, T;Shimizu, A
T细胞受体(TCR)和免疫球蛋白(Ig)基因的可变/多样性/连接(V[D]J)重组受目标基因座染色质以谱系和阶段特异的方式与重组酶的可及性调节。组蛋白乙酰化最近被认为是控制可及性的一个分子机制。在这里，我们研究了组蛋白乙酰化在小鼠TCR-γ基因发育调节重排中的作用，其中在胎儿到成人胸腺细胞发育过程中，主要重排从V Gamma3基因切换到V Gamma2基因。我们的结果表明，组蛋白乙酰化与可及性有关，因为符合胚系转录的胎儿V型Gamma3基因的组蛋白乙酰化在胎儿胸腺细胞中相对较高，但在完全高乙酰化基因座的成人胸腺细胞中变得特别低。此外，在成人骨髓来源的胸腺细胞发育过程中，组蛋白去乙酰化被特异组蛋白去乙酰化酶抑制剂曲古抑素A抑制，导致组蛋白乙酰化、生殖系转录、裂解和V-Gamma3基因重排的增加。这些数据表明，组蛋白乙酰化在功能上决定了V(D)J在体内重组的染色质可及性，染色质的表观遗传修饰在决定细胞命运的发育开关中起着直接作用。
Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TCR) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manner. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for histone acetylation in the developmentally regulated rearrangements of the mouse TCR-gamma gene, wherein predominant rearrangement is switched from V gamma3 to V gamma2 gene during the fetal to adult thymocyte development. Our results indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type V gamma3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically becomes low in adult thymocytes within the entirely hyperacetylated locus. Furthermore, inhibition of histone deacetylation during the development of adult bone marrow-derived thymocytes by a specific histone deacetylase inhibitor, trichostatin A, leads to elevated histone acetylation, germline transcription, cleavage, and rearrangement of the V gamma3 gene. These data demonstrate that histone acetylation functionally determines the chromatin accessibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in cell fate determination.