Demethylation of a specific hypersensitive site in the Th2 locus control region
Demethylation of a specific hypersensitive site in the Th2 locus control region
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DOI：
10.1073/pnas.0708293104
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发表时间：
2007-10-23
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Kim, Sean T.;Fields, Patrick E.;Flavell, Richard A.
越来越多的文献研究并暗示DNA甲基化是辅助性T细胞(Th)分化的关键表观遗传修饰。DNA甲基转移酶或甲基结合蛋白的缺失降低了许多细胞因子的表达，允许它们的异位表达，而特定CpG残基的甲基化足以阻止表达。在这里，我们描述了Th2细胞因子基因座控制区(LCR)的去甲基化事件。RAD50超敏部位7(RHS7)是LCR中的一个超敏部位，以STAT6依赖的方式甲基化，并且只在2型条件下刺激的细胞中发生。强大的去甲基化似乎需要IL-4受体通过STAT6和CD28的信号作用，但GATA3不能影响这一过程。最后，RHS7的氯甲基化与细胞分裂无关，与“主动”而不是被动的机制一致。综上所述，这些发现与2型分化程序中RHS7去甲基化和Th2 LCR激活紧密相关。
A growing body of literature has examined and implicated DNA methylation as a critical epigenetic modification in T helper (Th) cell differentiation. The absence of DNA methyltransferases or methyl-binding proteins derepresses many cytokine loci, allowing their ectopic expression, while methylation of specific CpG residues is sufficient to prevent expression. Here, we characterize demethylation events of the Th2 cytokine locus control region (LCR). rad50 hypersensitive site 7 (RHS7), a hypersensitive site within this LCR, becomes clemethylated in a STAT6-dependent manner and only in cells stimulated under type 2 conditions. Robust demethylation appears to require signaling contributions from both IL-4 receptor, via STAT6, and CD28, but it cannot be effected by GATA3. Finally, RHS7 is clemethylated independently of cell division, consistent with an '' active,'' rather than passive, mechanism. Taken together, these findings firmly connect RHS7 demethylation and Th2 LCR activation in the type 2 differentiation program.