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Recombination control of lymphocyte antigen receptor loci by chromati modification

通过染色质修饰控制淋巴细胞抗原受体位点的重组

基本信息

批准号：
14370056
负责人：
IKUTA Koichi
金额：
$ 9.54万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370056/
关键词：
cytokine Stat γδ T cell T cell antigen receptor signal transduction DNA recombination histone modification chromatin サイトカインヒストン修飾クロマチンサイトカインレセプタ

项目摘要

The IL-7 receptor (IL-7R) plays several critical roles in lymphocyte development by promoting proliferation and by inducing V(D)J,recombination in TCR and Ig loci. Previously, we have shown that Stat5 activated by the IL-7R binds to Jγ germline promoter and induces germline transcription of the TCRγ locus. An active Stat5 also rescued germline transcription and V-J recombination of this locus in IL-7Rα-/-thymocytes. 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. Our results demonstrated that CBP/p300 transcriptional,coactivators augment Stat5-induced germline transcription of the TCRγ locus by their intrinsic histone acetyltransferase activity. Concurrently, histones are hyperacetylated at transcriptionally-active Jγ segments in normal thymocyte precursors and Ba/F3 cells, but not in IL-7Rα-l-thymocytes. Cytokine stimulation rapidly induces the recruitment of Stat5 and histone acetylation at the endogenous Jγ segments in Ba/F3 cells. We also showed that forced expression of RAG1 and RAG2 selectively induces cleavage at the Jγ segment in Ba/F3 cells. Therefore, our study strongly supported the idea that Stat5 recruits the transcriptional coactivators to the Jγ germline promoter and controls the accessibility of the TCRγ locus by histone acetylation.

IL-7受体（IL-7R）通过促进淋巴细胞增殖和诱导TCR和Ig位点的V(D)J、重组，在淋巴细胞发育中起着关键作用。在此之前，我们已经证明被IL-7R激活的Stat5结合到Jγ胚系启动子上并诱导TCRγ位点的胚系转录。活跃的Stat5也可以挽救IL-7Rα-/-胸腺细胞中该位点的种系转录和V-J重组。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的作用。我们的研究结果表明，CBP/p300转录共激活因子通过其固有的组蛋白乙酰转移酶活性增强stat5诱导的TCRγ位点的种系转录。同时，在正常胸腺细胞前体和Ba/F3细胞中，组蛋白在转录活性的Jγ片段上高乙酰化，但在il - 7r α-l-胸腺细胞中没有。细胞因子刺激可快速诱导Ba/F3细胞内源性Jγ片段Stat5的募集和组蛋白乙酰化。我们还发现，在Ba/F3细胞中，RAG1和RAG2的强制表达选择性地诱导了Jγ片段的切割。因此，我们的研究有力地支持了Stat5将转录共激活因子募集到Jγ胚系启动子，并通过组蛋白乙酰化控制TCRγ位点的可及性的观点。