Recombination control of lymphocyte antigen receptor loci by chromati modification

IL-7受体（IL-7 R）通过促进增殖和诱导TCR和IG基因座中的V（D）J重组在淋巴细胞发育中起几种关键作用。以前，我们已经证明，由IL-7 R激活的Stat 5与Jγ生殖系启动子结合，并诱导TCRγ基因座的生殖系转录。活化的Stat 5也挽救了IL-7 R α-/-胸腺细胞中该位点的生殖系转录和V-J重组。为了确定将Stat 5诱导的生殖系转录与TCRγ位点的可及性联系起来的分子机制，我们表征了转录辅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转录辅激活因子通过其内在的组蛋白乙酰转移酶活性增强Stat 5诱导的TCRγ基因座的生殖系转录。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Jγ片段处高度乙酰化，但在IL-7 R α-l-胸腺细胞中则没有。细胞因子刺激可快速诱导Ba/F3细胞内源性Jγ片段Stat 5的募集和组蛋白乙酰化。我们还发现，RAG 1和RAG 2的强制表达选择性地诱导Ba/F3细胞中Jγ片段的切割。因此，我们的研究有力地支持了Stat 5将转录辅激活因子募集到Jγ生殖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。

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.