Tani-ichi Shizue, Satake Masanobu, Ikuta Koichi
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Int Immunol. 2009 Sep;21(9):1079-88. doi: 10.1093/intimm/dxp073. Epub 2009 Aug 3.
The IL-7R controls local accessibility of joining (J) gamma gene segments in the mouse TCRgamma locus by recruiting signal transducers and activators of transcription (STAT) 5 and transcriptional coactivators to the Jgamma germ line promoters and inducing histone acetylation and germ line transcription. Because STAT consensus motifs are conserved not only in the Jgamma promoters but also in the TCRgamma 3' enhancer (Egamma) elements, it is possible that STAT5 interacts with and activates Egamma. To address this question, we first showed that the lysine 4 residue of histone H3 is substantially methylated at Egamma1 and Egamma4 elements in wild-type early thymocytes and that the levels of the methylation are reduced in IL-7R alpha chain-deficient mice. We also showed that STAT5 has potential to elevate histone acetylation of the Egamma elements in a cytokine-dependent cell line by cytokine stimulation. Next, we demonstrated that STAT5 is recruited to the STAT consensus motifs in the Egamma elements after cytokine stimulation and that transcription factors Runt-related (Runx) and c-Myb are constitutively recruited to Egamma. Furthermore, we showed that STAT5 augments basal Egamma activity controlled by Runx and c-Myb. These results suggest that STAT5 is recruited to the consensus motifs in the Egamma elements by cytokine stimulation and augments basal Egamma activity independent of Runx and c-Myb. Therefore, this study implies that the Egamma elements might be activated in two successive steps, first by Runx and c-Myb and next by STAT5.
白细胞介素-7受体（IL-7R）通过招募信号转导和转录激活因子（STAT）5以及转录共激活因子至Jγ基因座的生殖系启动子，并诱导组蛋白乙酰化和生殖系转录，从而控制小鼠T细胞受体γ（TCRγ）基因座中连接（J）γ基因片段的局部可及性。由于STAT共有基序不仅在Jγ启动子中保守，而且在TCRγ 3'增强子（Eγ）元件中也保守，因此STAT5有可能与Eγ相互作用并激活Eγ。为了解决这个问题，我们首先表明，在野生型早期胸腺细胞的Eγ1和Eγ4元件处，组蛋白H3的赖氨酸4残基大量甲基化，而在IL-7Rα链缺陷小鼠中，这种甲基化水平降低。我们还表明，在细胞因子刺激下，STAT5有潜力提高细胞因子依赖性细胞系中Eγ元件的组蛋白乙酰化水平。接下来，我们证明了细胞因子刺激后，STAT5被招募至Eγ元件中的STAT共有基序，并且转录因子Runx相关（Runx）和c-Myb持续被招募至Eγ。此外，我们表明STAT5增强了由Runx和c-Myb控制的基础Eγ活性。这些结果表明，细胞因子刺激将STAT5招募至Eγ元件中的共有基序，并增强了独立于Runx和c-Myb的基础Eγ活性。因此，本研究表明Eγ元件可能在两个连续步骤中被激活，首先由Runx和c-Myb激活，其次由STAT5激活。
