Chen Lin, Chen Kaifu, Lavery Laura A, Baker Steven Andrew, Shaw Chad A, Li Wei, Zoghbi Huda Y
Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030.
Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, and.
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5509-14. doi: 10.1073/pnas.1505909112. Epub 2015 Apr 13.
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.
表观遗传机制，如DNA甲基化，可调节转录程序，使基因组在健康和疾病状态下应对发育和环境线索时具有灵活性。一个涉及表观遗传功能障碍的典型例子是产后神经发育障碍雷特综合征（RTT），它由编码甲基CpG结合蛋白2（MeCP2）的基因突变引起。尽管经过数十年的研究，MeCP2如何调节转录以及RTT特征为何在出生后6至18个月出现仍不清楚。在此，我们报告了对MeCP2的基因组结合、基因表达数据和DNA甲基化模式的综合分析。除了预期的在CG背景下与甲基化胞嘧啶（mCG）的高亲和力结合外，我们在成人大脑中发现了一种独特的表观遗传模式，即MeCP2与非CG背景下的甲基化胞嘧啶（mCH，其中H = A、C或T）大量结合。出乎意料的是，我们发现出生后mCH升高的基因在MeCP2疾病的小鼠模型中优先发生调控异常，这表明MeCP2在mCH位点的结合是体内调节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特有的，因为它需要出生后mCH的增加来指导MeCP2在mCG、mCH和非甲基化DNA元件之间的差异结合。值得注意的是，MeCP2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是一个与RTT病理生理学相关的基因。因此，本研究深入了解了控制MeCP2靶向的分子机制，并揭示了RTT症状延迟出现的原因。
