MeCP2 Binds to 5hmC Enriched within Active Genes and Accessible Chromatin in the Nervous System
MeCP2 Binds to 5hmC Enriched within Active Genes and Accessible Chromatin in the Nervous System
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DOI：
10.1016/j.cell.2012.11.022
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发表时间：
2012-12-21
期刊：
影响因子：
64.5
通讯作者：
Heintz, Nathaniel
中科院分区：
文献类型：
--
作者：
Mellen, Marian;Ayata, Pinar;Heintz, Nathaniel
神经元基因组中存在高水平的5-羟甲基胞嘧啶(5hmC)，这表明在中枢神经系统中解释5hmC的机制可能不同于胚胎干细胞中存在的机制。在这里，我们提供了定量的，全基因组分析5hmC，5-甲基胞嘧啶(5mC)，以及体内分化的CNS细胞类型的基因表达。我们报告了5HmC富含活性基因，令人惊讶的是，在这些区域观察到5mC的强烈耗尽。这些表观遗传标记对基因表达的贡献主要取决于细胞类型。我们确定甲基CpG结合蛋白2(MeCP2)是大脑中主要的5hmC结合蛋白，并证明MeCP2以类似的高亲和力结合含有5hmC和5mC的DNA。导致Rett综合征的突变R133C优先抑制5hmC结合。这些发现支持一种模型，在该模型中，5hmC和MeCP2构成了细胞特异性的表观遗传机制，以调节染色质结构和基因表达。
The high level of 5-hydroxymethylcytosine (5hmC) present in neuronal genomes suggests that mechanisms interpreting 5hmC in the CNS may differ from those present in embryonic stem cells. Here, we present quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo. We report that 5hmC is enriched in active genes and that, surprisingly, strong depletion of 5mC is observed over these regions. The contribution of these epigenetic marks to gene expression depends critically on cell type. We identify methyl-CpG-binding protein 2 (MeCP2) as the major 5hmC-binding protein in the brain and demonstrate that MeCP2 binds 5hmC- and 5mC-containing DNA with similar high affinities. The Rett-syndrome-causing mutation R133C preferentially inhibits 5hmC binding. These findings support a model in which 5hmC and MeCP2 constitute a cell-specific epigenetic mechanism for regulation of chromatin structure and gene expression.