MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome
MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome
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DOI：
10.1073/pnas.1505909112
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发表时间：
2015-04-28
影响因子：
11.1
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Chen, Lin;Chen, Kaifu;Zoghbi, Huda Y.
表观遗传机制，如DNA甲基化，调节转录程序，以提供基因组的灵活性，在健康和疾病的发展和环境的线索。涉及表观遗传功能障碍的一个主要例子是出生后神经发育障碍Rett综合征（RTT），这是由编码甲基CpG结合蛋白2（MeCP 2）的基因突变引起的。尽管经过数十年的研究，仍不清楚MeCP 2如何调节转录，以及为什么RTT特征在出生后6-18个月出现。在这里，我们报告的MeCP 2，基因表达数据和DNA甲基化模式的基因组结合的综合分析。除了预期的高亲和力结合甲基化胞嘧啶在CG的背景下（mCG），我们发现了一个独特的表观遗传模式的大量MeCP 2结合甲基化胞嘧啶在非CG的背景下（mCH，其中H = A，C，或T）在成人大脑。出乎意料的是，我们发现出生后获得升高mCH的基因在MeCP 2疾病的小鼠模型中优先失调，这表明MeCP 2在mCH位点的结合是调节体内神经元基因表达的关键。这种模式是成熟和成年神经系统所独有的，因为它需要出生后mCH的增加来引导mCG、mCH和非甲基化DNA元件之间的差异MeCP 2结合。值得注意的是，MeCP 2与mCH的结合亲和力高于非甲基化的相同DNA序列，从而影响Bdnf的水平，Bdnf是一种与RTT的病理生理学有关的基因。因此，这项研究提供了对控制MeCP 2靶向的分子机制的深入了解，并揭示了RTT症状的延迟发作。
Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6-18 months after birth. Here we report integrated analyses of genomic binding of MeCP2, gene-expression data, and patterns of DNA methylation. In addition to the expected high-affinity binding to methylated cytosine in the CG context (mCG), we find a distinct epigenetic pattern of substantial MeCP2 binding to methylated cytosine in the non-CG context (mCH, where H = A, C, or T) in the adult brain. Unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.