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Induction mechanism of V-J recombination by signaling molecules of the IL-7 receptor

IL-7受体信号分子诱导V-J重组的机制

基本信息

批准号：
11694264
负责人：
IKUTA Koichi
金额：
$ 3.78万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694264/
关键词：
cytokine receptor Stat γδT cell signal transduction DNA recombination histone acetylation transcriptional coactivator retrovirus STAT レトロウィルス

项目摘要

IL-7 receptor (IL-7R) plays critical roles in lymphocyte development by promoting survival and proliferation and by inducing V(D)J recombination in TCR and Ig loci. To identify the molecular mechanism of the induction of gene rearrangement by IL-7R, we characterized the role of Stat5 in the germline transcription of TCRγ genes. Our results demonstrated that IL-7R-activated Stat5 binds to consensus motifs in 5' regions of Jγ segments and induces germline transcripts. We also found that a constitutively-active form of Stat5 induces germline transcription, restores V-J recombination of TCRγ genes, and partially rescues T cell development from IL-7R^<-/-> T cell precursors, especially in favor of γδ T cells. Therefore, these results revealed a potential role of Stat5 in T cell development, and implied that Stat5 may control the accessibility of the TCRγ locus by the induction of germline transcripts. Next, to identify the molecular mechanism that links the Stat5-induced germline transcription to the accessibility of the TCRγ locus, we characterized the role of transcriptional coactivators and histone acetylation in TCRγ genes. We demonstrated that cytokine stimulation rapidly recruits Stat5 and transcriptional coactivators to the 5'Jγ germline promoter and increases histone acetylation, germline transcription, and accessibility in Ba/F3 cells. We also show that histone acetylation of the TCRγ locus is significantly reduced in IL-7R-deficient thymocyte precursors and that introduction of active Stat5 restores the histone acetylation and accessibility of the TCRγ locus. Therefore, these results suggested that Stat5 controls local accessibility of the Jγ region by recruiting the transcriptional coactivators and inducing histone acetylation. Our study also implied a potential role of Stat5 in the locus-wide accessibility control by the TCRγ enhancer (Eγ).

IL-7受体（IL-7R）通过促进淋巴细胞存活和增殖以及诱导TCR和Ig位点的V(D)J重组，在淋巴细胞发育中起着至关重要的作用。为了确定IL-7R诱导基因重排的分子机制，我们表征了Stat5在TCRγ基因种系转录中的作用。我们的研究结果表明，il - 7r激活的Stat5结合到Jγ片段5'区域的共识基序并诱导种系转录本。我们还发现，Stat5的组成活性形式诱导种系转录，恢复TCRγ基因的V-J重组，并部分地从IL-7R^<-/-> T细胞前体中拯救T细胞发育，特别是有利于γδ T细胞。因此，这些结果揭示了Stat5在T细胞发育中的潜在作用，并暗示Stat5可能通过诱导种系转录物来控制TCRγ位点的可及性。接下来，为了确定将stat5诱导的种系转录与TCRγ位点的可及性联系起来的分子机制，我们表征了转录共激活因子和组蛋白乙酰化在TCRγ基因中的作用。我们证明，细胞因子刺激可迅速将Stat5和转录共激活因子招募到5’jγ胚系启动子，并增加Ba/F3细胞的组蛋白乙酰化、胚系转录和可及性。我们还发现，在il - 7r缺陷胸腺细胞前体中，TCRγ位点的组蛋白乙酰化显著降低，激活Stat5的引入恢复了TCRγ位点的组蛋白乙酰化和可及性。因此，这些结果表明Stat5通过募集转录共激活因子和诱导组蛋白乙酰化来控制Jγ区域的局部可及性。我们的研究还暗示了Stat5在TCRγ增强子（e - γ）的全位点可及性控制中的潜在作用。