Distinct requirement of Runx complexes for TCRβ enhancer activation at distinct developmental stages.
Distinct requirement of Runx complexes for TCRβ enhancer activation at distinct developmental stages.
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DOI：
10.1038/srep41351
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发表时间：
2017-02-02
影响因子：
4.6
通讯作者：
Taniuchi I
中科院分区：
文献类型：
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作者：
Seo W;Muroi S;Akiyama K;Taniuchi I
TCRβ增强子，称为Eβ增强子，在Tcrb基因的V（D）J重组和转录中起关键作用。然而，在T细胞发育过程中，反式作用因子在Eβ活化中的协调作用仍然没有表征。在这里，我们描述了Runx复合物在调节Eβ功能中的作用。Eβ内两个Runx结合基序之一的单一突变严重损害了未成熟胸腺细胞起始阶段的Tcrb活化。然而，在这种单一Runx位点突变下发育的成熟胸腺细胞中TCRβ表达水平与对照相似。相反，两个Runx基序的突变消除了Eβ活性，表明Runx复合物结合对启动Eβ活化至关重要。在表达具有重排的V（D）J结构的Tcrb的细胞中，Runx复合物被抑制以维持TCRβ表达，而Eβ本身是TCRβ表达所持续需要的。这些发现表明Runx复合物在起始阶段是Eβ激活所必需的，但在以后的发育阶段不是维持Eβ活性所必需的。总的来说，我们的结果表明，反式作用因子对Eβ活性的需求是有差异的，这取决于发育阶段和细胞活化状态。
A TCRβ enhancer, known as the Eβ enhancer, plays a critical role in V(D)J recombination and transcription of the Tcrb gene. However, the coordinated action of trans-acting factors in the activation of Eβ during T cell development remains uncharacterized. Here, we characterized the roles of Runx complexes in the regulation of the Eβ function. A single mutation at one of the two Runx binding motifs within the Eβ severely impaired Tcrb activation at the initiation phase in immature thymocytes. However, TCRβ expression level in mature thymocytes that developed under such a single Runx site mutation was similar to that of the control. In contrast, mutations at two Runx motifs eliminated Eβ activity, demonstrating that Runx complex binding is essential to initiate Eβ activation. In cells expressing Tcrb harboring rearranged V(D)J structure, Runx complexes are dispensable to maintain TCRβ expression, whereas Eβ itself is continuously required for TCRβ expression. These findings imply that Runx complexes are essential for Eβ activation at the initiation phase, but are not necessary for maintaining Eβ activity at later developmental stages. Collectively, our results indicate that the requirements of trans-acting factor for Eβ activity are differentially regulated, depending on the developmental stage and cellular activation status.