Intragenic DNA methylation prevents spurious transcription initiation
Intragenic DNA methylation prevents spurious transcription initiation
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DOI：
10.1038/nature21373
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发表时间：
2017-03-02
期刊：
影响因子：
64.8
通讯作者：
Oliviero, Salvatore
中科院分区：
文献类型：
--
作者：
Neri, Francesco;Rapelli, Stefania;Oliviero, Salvatore
在哺乳动物中，DNA甲基化主要发生在CpG二核苷酸。启动子甲基化抑制基因表达，但基因体DNA甲基化在高表达基因中的功能作用尚未阐明。在这里，我们表明，在小鼠胚胎干细胞中，Dnmt3b依赖的基因内DNA甲基化保护基因体免受虚假RNA聚合酶II进入和隐蔽转录起始的影响。使用不同的全基因组方法，我们证明了这种Dnmt3b功能依赖于其酶活性和H3K36me3对基因体的募集。此外，假转录物可以被RNA外泌体复合物降解或加帽、聚腺苷酸化并递送至核糖体以产生异常蛋白质。因此，延长RNA聚合酶II触发了一种涉及SetD2、H3K36me3、Dnmt3b和DNA甲基化的表观遗传串扰机制，以确保基因转录起始的保真度，并暗示癌症中的基因内低甲基化。
In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.