期刊
NATURE GENETICS
卷 51, 期 2, 页码 217-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0306-6
关键词
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资金
- Helmholtz Foundation
- Deutsche Forschungsgemeinschaft [GR475/221, SFB1036]
- CellNetworks Cluster of Excellence (EcTop 5)
- DKFZ-MOST programme
- Baden-Wurttemberg Stiftung [NCRNA_025]
- European Research Council (ERC) DNAdemethylase
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.
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