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首页> 外文期刊>Nature >CTCF-promoted RNA polymerase Ⅱ pausing links DNA methylation to splicing
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CTCF-promoted RNA polymerase Ⅱ pausing links DNA methylation to splicing

机译：CTCF促进的RNA聚合酶Ⅱ暂停将DNA甲基化与剪接联系起来

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摘要

Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons bymediating local RNA polymerase Ⅱ pausing both ina mammalian model system for alternative splicing, CD45, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.
机译：前信使RNA的选择性剪接是真核细胞转录组扩增的关键特征，但对其调控了解甚少。剪接体组装以共转录方式发生，从而增加了DNA结构可能直接影响其他剪接的可能性。支持这种关联，最近的报道已经鉴定出相对于内含子，不同的组蛋白甲基化模式，增加的核小体占据和丰富的外显子DNA甲基化。而且，转录伸长率与选择性剪接有关。在这里，我们提供了第一个证据，即DNA结合蛋白CCCTC结合因子（CTCF）可以通过介导局部RNA聚合酶Ⅱ促进哺乳动物上游系统的选择性剪接，CD45和全基因组范围内的中下游弱外显子的包涵。我们进一步表明，CTCF与CD45外显子5的结合被DNA甲基化抑制，从而导致对外显子5包涵体的相互影响。这些发现为通过遗传表观遗传标记的剪接结果的发育调控提供了机械基础。

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  • 来源
    《Nature》 |2011年第7371期|p.74-79|共6页
  • 作者

    Sanjeev Shukla; Ersen Kavak; Melissa Gregory; Masahiko Imashimizu; Bojan Shutinoski; Mikhail Kashlev; Philipp Oberdoerffer; Rickard Sandberg; Shalini Oberdoerffer;

  • 作者单位

    Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Department of Cell and Molecular Biology, Karolinskalnstitutet,SE-171 77 Stockholm, Sweden,Ludwig Institute for Cancer Research, SE-171 77, Stockholm, Sweden;

    Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Center for Cancer Research, Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Center for Cancer Research, Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

    Department of Cell and Molecular Biology, Karolinskalnstitutet,SE-171 77 Stockholm, Sweden,Ludwig Institute for Cancer Research, SE-171 77, Stockholm, Sweden;

    Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA;

  • 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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