CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.
CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.
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DOI：
10.1038/nature10442
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发表时间：
2011-11-03
期刊：
影响因子：
64.8
通讯作者：
Oberdoerffer S
中科院分区：
文献类型：
--
作者：
Shukla S;Kavak E;Gregory M;Imashimizu M;Shutinoski B;Kashlev M;Oberdoerffer P;Sandberg R;Oberdoerffer S
预上音符RNA的替代剪接是真核细胞中转录组扩展的关键特征，但其调节知之甚少。剪接体组装在共转录上发生，从而增加了DNA结构直接影响替代剪接的可能性。在支持这种关联的情况下，最近的报道确定了相对于内含子的外显子处的不同组蛋白甲基化模式，核小体占用率升高和富集的DNA甲基化。此外，转录伸长率与替代剪接有关。在这里，我们提供了第一个证据，表明DNA结合蛋白CCCTC结合因子（CTCF）可以通过介导局部RNA聚合酶II暂停在哺乳动物模型系统中以用于替代剪接，CD45和Genome-genome-genome-genome-genome---基因组 - 宽的。我们进一步表明，DNA甲基化抑制了与CD45外显子5结合的CTCF，从而导致对外显子5包含的相互影响。这些发现为通过可遗传的表观遗传标记对剪接结果的发育调节提供了机械基础。
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 by mediating local RNA polymerase II pausing both in a 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.
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影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
人类中的相互内含子和外显子组蛋白修饰区。
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作者：
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通讯作者：
Kashlev, Mikhail
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作者：
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通讯作者：
Ren, Bing
影响因子：
4.8
作者：
Awrey, DE;Weilbaecher, RG;Edwards, AM
通讯作者：
Edwards, AM