MeCP2 binds to mCH as neurons mature, influencing transcription and onset of Rett syndrome [mRNA-Seq]

The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding Methyl-CpG-binding Protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 actually regulates transcription or why RTT features appear only 6-18 months after birth. We examined MeCP2 binding to methylated cytosine in the CH context (mCH, where H = A, C, or T) in the adult mouse brain and found that MeCP2 binds these mCH sites, influencing nucleosome positioning and transcription. Strikingly, this pattern is unique to the mature nervous system, as it requires the increase in mCH after birth to reveal differences in MeCP2 binding to mCG, mCH, and non-methylated DNA elements. This study provides insight into the molecular mechanism governing MeCP2 targeting and how this targeting might contribute to the delayed onset of RTT symptoms. mRNA-Seq were conducted from 7-week-old hypothalamus from MeCP2 knockout mice and their age and genetic background matched wild types control mice. Additonal mRNA-Seq were conducted from 7-week-old hypothalamus from MeCP2 transgenic mice and their age and genetic background matched wild types control mice.产后神经发育障碍瑞特综合征（Rett syndrome, RTT）是由编码甲基CpG结合蛋白2（Methyl-CpG-binding Protein 2, MeCP2）的基因突变所引发的。尽管已有数十年的研究积累，学界仍未明确MeCP2调控转录的实际机制，以及瑞特综合征的症状为何仅在出生后6至18个月才显现。本研究针对成年小鼠大脑中CH背景下的甲基化胞嘧啶（mCH，其中H代表A、C或T）与MeCP2的结合情况展开检测，发现MeCP2可结合此类mCH位点，并对核小体定位及转录过程产生影响。值得注意的是，该结合模式仅存在于成熟神经系统中——这是因为该过程需要出生后mCH水平的升高，才能凸显出MeCP2与mCG、mCH以及非甲基化DNA元件的结合差异。本研究为解析调控MeCP2靶向的分子机制，以及该靶向过程如何促成瑞特综合征症状的迟发性发作提供了新的见解。本研究对7周龄MeCP2敲除小鼠及其同年龄、遗传背景匹配的野生型对照小鼠的下丘脑组织开展了mRNA测序（mRNA-Seq）。此外，还对7周龄MeCP2转基因小鼠及其同年龄、遗传背景匹配的野生型对照小鼠的下丘脑组织进行了额外的mRNA测序实验。