Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK.
Mol Cell. 2010 Feb 26;37(4):457-68. doi: 10.1016/j.molcel.2010.01.030.
MeCP2 is a nuclear protein with an affinity for methylated DNA that can recruit histone deacetylases. Deficiency or excess of MeCP2 causes severe neurological problems, suggesting that the number of molecules per cell must be precisely regulated. We quantified MeCP2 in neuronal nuclei and found that it is nearly as abundant as the histone octamer. Despite this high abundance, MeCP2 associates preferentially with methylated regions, and high-throughput sequencing showed that its genome-wide binding tracks methyl-CpG density. MeCP2 deficiency results in global changes in neuronal chromatin structure, including elevated histone acetylation and a doubling of histone H1. Neither change is detectable in glia, where MeCP2 occurs at lower levels. The mutant brain also shows elevated transcription of repetitive elements. Our data argue that MeCP2 may not act as a gene-specific transcriptional repressor in neurons, but might instead dampen transcriptional noise genome-wide in a DNA methylation-dependent manner.
MECP2 是一种与甲基化 DNA 具有亲和力的核蛋白，能够募集组蛋白去乙酰化酶。MECP2 的缺乏或过量会导致严重的神经问题，这表明每个细胞中的分子数量必须精确调控。我们定量了神经元核中的 MECP2，发现它的含量几乎与组蛋白八聚体一样丰富。尽管含量如此之高，但 MECP2 还是优先与甲基化区域结合，高通量测序显示其在全基因组范围内的结合轨迹与甲基化 CpG 密度相关。MECP2 的缺乏会导致神经元染色质结构的全局变化，包括组蛋白乙酰化水平升高和组蛋白 H1 的两倍增加。这些变化在胶质细胞中都检测不到，而 MECP2 在胶质细胞中的含量较低。突变体大脑中还表现出重复元件转录水平的升高。我们的数据表明，MECP2 在神经元中可能不是作为基因特异性转录抑制剂发挥作用，而是以依赖 DNA 甲基化的方式在全基因组范围内抑制转录噪声。
