Regulation of mRNA splicing by MeCP2 via epigenetic modifications in the brain.
Regulation of mRNA splicing by MeCP2 via epigenetic modifications in the brain.
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MeCP2 通过大脑中的表观遗传修饰调节 mRNA 剪接。
DOI：
10.1038/srep42790
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发表时间：
2017-02-17
影响因子：
4.6
通讯作者：
Qiu Z
中科院分区：
文献类型：
--
作者：
Cheng TL;Chen J;Wan H;Tang B;Tian W;Liao L;Qiu Z
X连锁基因甲基CpG结合蛋白2（MECP 2）的突变是Rett综合征（RTT）的主要病因。重复的MECP 2基因片段导致人类严重的自闭症症状。MECP 2编码蛋白甲基-CpG-结合蛋白2（MeCP 2）参与转录调控、microRNA加工和mRNA剪接。然而，MeCP 2参与神经元mRNA剪接的分子机制仍然很难理解。在这项工作中，我们发现大多数MeCP 2相关蛋白参与mRNA剪接使用质谱分析与多个样品从Mecp 2-null大鼠脑，小鼠原代神经元和人类细胞系。我们进一步表明，在培养的皮层神经元中Mecp 2敲低导致mRNA选择性剪接的广泛变化。ChIP-seq数据集的分析表明，MeCP 2调节的外显子显示出特定的表观遗传特征，与未受影响的神经元相比，DNA修饰5-羟甲基胞嘧啶（5 hmC）和组蛋白修饰H3 K4 me 3富集在下调的外显子中，而H3 K36 me 3特征富集在Mecp 2敲低神经元中上调的外显子中。功能分析表明，含有MeCP 2调控外显子的基因主要参与突触功能和mRNA剪接。这些结果表明MeCP 2通过与5 hmC相互作用和组蛋白标记的表观遗传变化来调节mRNA剪接，并提供了MeCP 2介导的mRNA剪接在神经系统中的功能见解。
Mutations of X-linked gene Methyl CpG binding protein 2 (MECP2) are the major causes of Rett syndrome (RTT), a severe neurodevelopmental disorder. Duplications of MECP2-containing genomic segments lead to severe autistic symptoms in human. MECP2-coding protein methyl-CpG-binding protein 2 (MeCP2) is involved in transcription regulation, microRNA processing and mRNA splicing. However, molecular mechanisms underlying the involvement of MeCP2 in mRNA splicing in neurons remain largely elusive. In this work we found that the majority of MeCP2-associated proteins are involved in mRNA splicing using mass spectrometry analysis with multiple samples from Mecp2-null rat brain, mouse primary neuron and human cell lines. We further showed that Mecp2 knockdown in cultured cortical neurons led to widespread alternations of mRNA alternative splicing. Analysis of ChIP-seq datasets indicated that MeCP2-regulated exons display specific epigenetic signatures, with DNA modification 5-hydroxymethylcytosine (5hmC) and histone modification H3K4me3 are enriched in down-regulated exons, while the H3K36me3 signature is enriched in exons up-regulated in Mecp2-knockdown neurons comparing to un-affected neurons. Functional analysis reveals that genes containing MeCP2-regulated exons are mainly involved in synaptic functions and mRNA splicing. These results suggested that MeCP2 regulated mRNA splicing through interacting with 5hmC and epigenetic changes in histone markers, and provide functional insights of MeCP2-mediated mRNA splicing in the nervous system.