Recombination control of lymphocyte antigen receptor loci by chromati modification

IL-7受体(IL-7R)通过促进细胞增殖和诱导V(D)J基因在Tcr和Ig基因座的重组，在淋巴细胞发育中发挥重要作用。以前，我们已经证明了由IL-7R激活的Stat5与Jγ生殖系启动子结合并诱导TCRTCRγ基因座的生殖系转录。激活的STAT5也挽救了IL-7Rα-/-胸腺细胞中该基因的生殖系转录和V-J重组。为了确定STAT5诱导的生殖系转录与TCRTcRγ位点的可及性之间的联系的分子机制，我们研究了转录辅助激活因子和组蛋白乙酰化的作用。我们的结果表明，CBP/p300转录共激活子通过其固有的组蛋白乙酰转移酶活性增强了STAT5诱导的TCRTcrγ基因座的胚系转录。同时，在正常胸腺细胞前体细胞和BA/F3细胞中，组蛋白在转录活性较高的Jγ片段处发生超乙酰化，但在IL-7Rα-L胸腺细胞中不出现。细胞因子刺激可迅速诱导BA/F3细胞内源性J-γ片段STAT5和组蛋白乙酰化。我们还发现，强制表达RAG1和RAG2选择性地诱导了BA/F3细胞J-γ片段的切割。因此，我们的研究有力地支持了STAT5将转录共激活因子招募到Jγ生殖系启动子并通过组蛋白乙酰化来控制γ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.