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.

中文翻译：

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GADD45A结合R环并将TET1募集到CpG岛启动子。

R环是丰富的CpG岛（CGIs），可以调节染色质状态^1-8的DNA-RNA杂种。尚不清楚特定表观遗传读者如何识别和解释R环。在这里，我们显示GADD45A（生长停滞和DNA损伤蛋白45A）直接与R环结合，并通过募集TET1（十一个11易位1）来介导局部DNA去甲基化。研究抑癌剂TCF21（参考文献⁹），我们发现反义长非编码（lncRNA）TARID（TCF21反义RNA诱导启动子去甲基化）在TCF21启动子上形成R环。GADD45A与R环的结合会触发局部DNA脱甲基和TCF21表达。TARID转录，R环形成，DNA脱甲基和TCF21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，并且在RNase H1耗尽后其水平会增加。胚胎干细胞中的基因组图谱鉴定了CGI处的数千个R环依赖性TET1结合位点。我们建议GADD45A是一个表观遗传的R环阅读器，它将去甲基化机制募集到启动子CGI。