Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition.
Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition.
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尽管DNA甲基化在基因启动子区域的转录抑制功能已得到充分确立，但基因体区域中进化上保守且广泛分布的DNA甲基化的功能仍未完全被理解。在此，我们表明DNA甲基化在包含的可变剪接外显子（ASEs）中富集，并且DNA甲基化的抑制会导致ASEs的异常剪接。甲基-CpG结合蛋白MeCP2在包含的ASEs中富集，特别是那些甲基化程度也很高的外显子，并且DNA甲基化的抑制会破坏MeCP2对外显子的特异性靶向。有趣的是，MeCP2的缺失会导致组蛋白乙酰化增加和异常的ASE跳跃事件。我们进一步表明，组蛋白去乙酰化酶（HDAC）活性的抑制会导致外显子跳跃，且与MeCP2敲低所导致的外显子跳跃有高度显著的重叠。总之，我们的数据表明基因内DNA甲基化在外显子界定中起作用，以调节可变RNA剪接，并可通过招募多功能蛋白MeCP2来增强外显子识别，从而通过后续招募HDACs维持局部组蛋白的低乙酰化状态。
Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs), and that inhibition of DNA methylation results in aberrant splicing of ASEs. The methyl-CpG-binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased histone acetylation and aberrant ASE-skipping events. We further show that inhibition of histone deacetylase (HDAC) activity leads to exon skipping that shows a highly significant degree of overlap with that caused by MeCP2 knockdown. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs.
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