Regulation of TCR Vγ2 gene rearrangement by the helix-loop-helix protein, E2A.
Regulation of TCR Vγ2 gene rearrangement by the helix-loop-helix protein, E2A.
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螺旋-环-螺旋蛋白 E2A 对 TCR Vγ2 基因重排的调节。
DOI：
10.1093/intimm/dxr005
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Agata Y
中科院分区：
文献类型：
--
作者：
Nozaki M;Wakae K;Tamaki N;Sakamoto S;Ohnishi K;Uejima T;Minato N;Yanagihara I;Agata Y
IG和TCR基因的V（D）J重组受到靶基因染色质可及性的严格调控，具有谱系特异性和阶段特异性。在小鼠TCRγ基因座中，在成年胸腺中Vγ2基因重排比Vγ3重排占优势。这种优先重排可能是由于单个Vγ基因的差异可及性，因为Vγ基因的生殖系转录和组蛋白乙酰化水平与成年胸腺细胞中的重排频率密切相关。然而，负责Vγ基因重排的差异调节的因素在很大程度上是未知的。在这项研究中，我们证明了在缺乏碱性螺旋-环-螺旋蛋白E2 A的小鼠中，成年胸腺中的Vγ2重排显著减少。重排减少可能是由于Vγ2染色质可及性降低所致，因为Vγ2基因的生殖系转录和组蛋白乙酰化以E2 A剂量依赖性方式减少。我们进一步证明了E2 A在体内结合在Vγ2基因周围，并且我们鉴定了两个典型的E-box位点，E2 A可以在体外与Vγ2基因下游结合。此外，这两个E-box位点具有在E2 A过表达时激活转录的能力。这些数据表明，E2 A直接结合并增加Vγ2染色质的可及性，从而促进成年胸腺中的Vγ2重排。
V(D)J recombination of Ig and TCR genes is strictly regulated by the accessibility of target gene chromatin in a lineage- and stage-specific manner. In the mouse TCRγ locus, rearrangement of the Vγ2 gene predominates over Vγ3 rearrangement in the adult thymus. This preferential rearrangement is likely due to the differential accessibility of the individual Vγ genes, because the levels of germ line transcription and histone acetylation of the Vγ genes are well correlated with the rearrangement frequency in adult thymocytes. However, factors responsible for the differential regulation of the Vγ gene rearrangement have been largely unknown. In this study, we demonstrated that Vγ2 rearrangement in the adult thymus was substantially reduced in mice deficient for the basic helix-loop-helix protein, E2A. The decreased rearrangement is likely caused by the reduced accessibility of Vγ2 chromatin, since germ line transcription and histone acetylation of the Vγ2 gene were reduced in an E2A dosage-dependent manner. We further showed that E2A bound around the Vγ2 genein vivoand we identified two canonical E-box sites downstream of Vγ2, to which E2A can bindin vitro. Furthermore, these two E-box sites had the ability to activate transcription upon E2A over-expression. These data suggest that E2A directly binds to and increases accessibility of Vγ2 chromatin, thereby facilitating Vγ2 rearrangement in the adult thymus.