期刊
NATURE
卷 516, 期 7531, 页码 436-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13787
关键词
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资金
- Wellcome Trust [091805/Z/10/Z]
- European Research Council [339270-polyloop]
- Marie Curie Actions grant from EU FP7 (REA grant) [327985]
The formation of R-loops is a natural consequence of the transcription process, caused by invasion of the DNA duplex by nascent transcripts. These structures have been considered rare transcriptional by-products with potentially harmful effects on genome integrity owing to the fragility of the displaced DNA coding strand(1). However, R-loops may also possess beneficial effects, as their widespread formation has been detected over CpG island promoters in human genes(2,3). Furthermore, we have previously shown that R-loops are particularly enriched over G-rich terminator elements. These facilitate RNA polymerase II (Pol II) pausing before efficient termination(4). Here we reveal an unanticipated link between R-loops and RNA-interference-dependent H3K9me2 formation over pause-site termination regions in mammalian protein-coding genes. We show that R-loops induce antisense transcription over these pause elements, which in turn leads to the generation of double-stranded RNA and the recruitment of DICER, AGO1, AGO2 and the G9a histone lysine methyltransferase. Consequently, an H3K9me2 repressive mark is formed and heterochromatin protein 1 gamma (HP1 gamma) is recruited, which reinforces Pol II pausing before efficient transcriptional termination. We predict that R-loops promote a chromatin architecture that defines the termination region for a substantial subset of mammalian genes.
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