GADD45A binds R-loops and recruits TET1 to CpG island promoters
GADD45A binds R-loops and recruits TET1 to CpG island promoters
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DOI：
10.1038/s41588-018-0306-6
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发表时间：
2019-02-01
期刊：
影响因子：
30.8
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
--
作者：
Arab, Khelifa;Karaulanov, Emil;Niehrs, Christof
R环是在CpG岛（CGI）处富集的DNA-RNA杂合体，其可以调节染色质状态（1-8）。R环如何被特定的表观遗传阅读器识别和解释是未知的。在这里，我们表明，GADD 45 A（生长停滞和DNA损伤蛋白45 A）直接结合到R环，并通过招募TET 1（10 - 11易位1）介导局部DNA去甲基化。研究肿瘤抑制因子TCF 21（参考文献）(9))结果发现，TCF 21反义RNA诱导启动子去甲基化（antisense RNA inducing promoter demethylation，TARID）在TCF 21启动子上形成了一个R环。GADD 45 A与R环的结合触发局部DNA去甲基化和TCF 21表达。TARID转录、R环形成、DNA去甲基化和TCF 21表达在细胞周期中依次进行。氧化的DNA去甲基化中间体在基因组R环处富集，并且它们的水平在RNase H1耗尽时增加。胚胎干细胞的基因组分析鉴定了CGIs上数千个R环依赖性TET 1结合位点。我们认为GADD 45 A是一个表观遗传R环阅读器，它将去甲基化机制招募到启动子CGIs。
R-loops are DNA-RNA hybrids enriched at CpG islands (CGIs) that can regulate chromatin states(1-8). How R-loops are recognized and interpreted by specific epigenetic readers is unknown. Here we show that GADD45A (growth arrest and DNA damage protein 45A) binds directly to R-loops and mediates local DNA demethylation by recruiting TET1 (ten-eleven translocation 1). Studying the tumor suppressor TCF21 (ref.(9)), we find that antisense long noncoding (lncRNA) TARID (TCF21 antisense RNA inducing promoter demethylation) forms an R-loop at the TCF21 promoter. Binding of GADD45A to the R-loop triggers local DNA demethylation and TCF21 expression. TARID transcription, R-loop formation, DNA demethylation, and TCF21 expression proceed sequentially during the cell cycle. Oxidized DNA demethylation intermediates are enriched at genomic R-loops and their levels increase upon RNase H1 depletion. Genomic profiling in embryonic stem cells identifies thousands of R-loop-dependent TET1 binding sites at CGIs. We propose that GADD45A is an epigenetic R-loop reader that recruits the demethylation machinery to promoter CGIs.