Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi, Korea.
Clin Exp Med. 2010 Sep;10(3):143-52. doi: 10.1007/s10238-009-0083-8. Epub 2009 Dec 1.
STAT6 transcription factor, which has been implicated in commitment to Th2, is known to be activated by IL-4 and IL-13. Accordingly, STAT6 is primarily responsible for the transcriptional effects of IL-4 and IL-13. STAT6-deficient mice are known to have defective IL-4-mediated functions, such as B cell proliferation, Th2 cell development and IgE secretion; therefore, they primarily contain the Th1 phenotype. However, the mechanism responsible for regulation of STAT6 expression transcriptionally and post-transcriptionally has yet to be elucidated. Here, we characterized the human STAT6 promoter gene and found that the transcriptional regulatory elements CCAAT and ATF were important for the STAT6 promoter activity. Direct sequencing analysis revealed that the 13 GT repeat allelic variation in noncoding exon 1 of the STAT6 gene appeared more frequently in 91 patients with asthma or rheumatoid arthritis than the 15 GT repeat variation, which is the dominant phenotype in healthy controls. However, it appears that this allelic variation did not affect the STAT6 transcriptional activity. Interestingly, treatment with a DNA methyltransferase inhibitor markedly increased the expression of STAT6 mRNA and protein in human primary T cells. In contrast, IFN-gamma treatment significantly repressed the STAT6 transcriptional activity. Therefore, the present study provides insight into the molecular basis of STAT6 expression, and in particular, demonstrates that STAT6 expression is associated with DNA hypermethylation rather than promoter polymorphisms or allelic variations.
STAT6 转录因子已被证实参与 Th2 细胞的定向分化，其激活依赖于 IL-4 和 IL-13。因此，STAT6 主要负责 IL-4 和 IL-13 的转录效应。STAT6 缺陷型小鼠表现出 IL-4 介导的功能缺陷，如 B 细胞增殖、Th2 细胞发育和 IgE 分泌；因此，它们主要表现为 Th1 表型。然而，STAT6 表达转录和转录后调节的机制尚未阐明。在这里，我们对人类 STAT6 启动子基因进行了特征分析，发现 CCAAT 和 ATF 转录调控元件对于 STAT6 启动子活性很重要。直接测序分析显示，STAT6 基因非编码外显子 1 中的 13 GT 重复等位基因变异在哮喘或类风湿关节炎患者中比健康对照组中占主导地位的 15 GT 重复变异更为常见。然而，这种等位基因变异似乎并不影响 STAT6 的转录活性。有趣的是，DNA 甲基转移酶抑制剂处理显著增加了人原代 T 细胞中 STAT6 mRNA 和蛋白的表达。相反，IFN-γ处理显著抑制了 STAT6 的转录活性。因此，本研究为 STAT6 表达的分子基础提供了新的见解，特别是表明 STAT6 表达与 DNA 超甲基化有关，而不是与启动子多态性或等位基因变异有关。
