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Intragenic DNA methylation prevents spurious transcription initiation

机译：基因内DNA甲基化可防止伪造转录起始

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摘要

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.
机译：在哺乳动物中，DNA甲基化主要发生在CpG二核苷酸处。启动子的甲基化抑制基因表达，但是在高度表达的基因中基因体DNA甲基化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杂散RNA聚合酶II进入和隐秘转录起始。使用不同的全基因组方法，我们证明了Dnmt3b的功能取决于其酶促活性以及H3K36me3对基因体的募集。此外，伪造的转录物可以被RNA外泌体复合物降解，也可以被封端，聚腺苷酸化，然后传递至核糖体以产生异常蛋白。因此，延长的RNA聚合酶II触发了涉及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。

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  • 来源
    《Nature》 |2017年第7643期|72-77|共6页
  • 作者

    Neri Francesco; Rapelli Stefania; Krepelova Anna; Incarnato Danny; Parlato Caterina; Basile Giulia; Maldotti Mara; Anselmi Francesca; Oliviero Salvatore;

  • 作者单位

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy|Leibniz Inst Aging FLI, Beutenbergstr 11, D-07745 Jena, Germany;

    Univ Torino, Dipartimento Sci Vita & Biol Sistemi, Via Accademia Albertina 13, I-10123 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy|Univ Torino, Dipartimento Sci Vita & Biol Sistemi, Via Accademia Albertina 13, I-10123 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy|Univ Torino, Dipartimento Sci Vita & Biol Sistemi, Via Accademia Albertina 13, I-10123 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy|Univ Torino, Dipartimento Sci Vita & Biol Sistemi, Via Accademia Albertina 13, I-10123 Turin, Italy;

    Human Genet Fdn HuGeF, Via Nizza 52, I-10126 Turin, Italy|Univ Torino, Dipartimento Sci Vita & Biol Sistemi, Via Accademia Albertina 13, I-10123 Turin, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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