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CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing

热1 dechang 添加于 2011-11-5 08:39 | 4631 次阅读 | 0 个评论

作者
Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S
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 histonemethylation patterns, elevated nucleosome occupancy and enriched DNAmethylation 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 in amammalianmodel systemfor 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 amechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.
详细资料
- 文献种类: Journal Article
- 期刊名称: Nature
- 期刊缩写: Nature
- 期卷页: 2011年第479卷第7371期 74-79页
- ISBN: 0028-0836
学科领域生物医药 » 生物学
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CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing

dechang 的文献笔记订阅

信使RNA前体可变剪接是真核细胞转录的一个主要特点，但其调控知之甚少。剪接体组装与转录同步进行，提示DNA结构可能直接影响可变剪接。最近的报告支持这样一个关联，已经确定相对于内含子，外显子具有不同的组蛋白甲基化模式，升高的核小体占用和丰富的DNA甲基化。此外，转录延伸速率也与可变剪接相关。本文首次提供证据，一种DNA结合蛋白， CCCTC结合因子（ CTCF ），通过在哺乳动物模式系统介导局部和全基因组RNA聚合酶II暂停实现CD45可变剪接时促进上游弱外显子包含。进一步的研究表明CD45的外显子5与CTCF的结合受到DNA甲基化抑制，从而导致第5外显子包含的相互影响。这些发现提供了通过可遗传的表观遗传标记影响拼接的发育调控的基础。

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