Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment.
Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment.
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DOI：
10.1038/ncomms15134
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发表时间：
2017-05-08
影响因子：
16.6
通讯作者：
Rasko JEJ
中科院分区：
文献类型：
--
作者：
Wong JJ;Gao D;Nguyen TV;Kwok CT;van Geldermalsen M;Middleton R;Pinello N;Thoeng A;Nagarajah R;Holst J;Ritchie W;Rasko JEJ
虽然内含子保留（IR）被认为是一种广泛保守且独特的基因表达控制机制，但对其调控却知之甚少。在这里，我们证明 DNA 甲基化直接调节 IR。我们还发现保留内含子剪接点附近 MeCP2 的占据量减少，反映了这些位点 DNA 甲基化的减少。因此，组织和细胞中 MeCP2 的消耗会增强 IR。通过使用质谱和 RNA 共沉淀分析 MeCP2 相互作用组，我们证明剪接点附近 MeCP2 结合的减少通过减少剪接因子（包括 Tra2b）的募集和增加 RNA 聚合酶 II 停滞来促进 IR。这些结果表明 IR 与较慢的转录延伸率之间存在关联，这反映了低效的剪接因子招募。总之，我们的结果强化了涉及 IR 的选择性剪接和基因表达的表观遗传控制之间的相互依赖性。内含子保留是一种控制基因表达的保守机制，但对其调控知之甚少。在这里，作者提供了 DNA 甲基化调节内含子保留的证据，并发现受影响剪接点附近的 MeCP2 占用和剪接因子招募减少。
While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression. Intron retention is a conserved mechanism that controls gene expression but its regulation is poorly understood. Here, the authors provide evidence that DNA methylation regulates intron retention and find reduced MeCP2 occupancy and splicing factor recruitment near affected splice junctions.