Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome. MeCP2 is thought to regulate gene transcription by binding to methylated DNA broadly across the genome. Here, using cleavage under target and release under nuclease assays in the adult mouse cortex, we show that MeCP2 strongly binds to specific gene enhancers that we call MeCP2-binding hotspots (MBHs). Unexpectedly, we find that MeCP2 binding to MBHs occurs in a DNA methylation-independent manner at MBHs. Multiple MBH sites surrounding genes mediate the transcriptional repression of genes enriched for neuronal functions. We show that MBHs regulate genes irrespective of genic methylation levels, suggesting that MeCP2 controls transcription via an intragenic methylation-independent mechanism. Hence, disruption of intragenic methylation-independent gene regulation by MeCP2 may in part underlie Rett syndrome.

甲基 CpG 结合蛋白 2 （MeCP2） 突变会导致 Rett 综合征。MeCP2 被认为通过与整个基因组中的甲基化 DNA 广泛结合来调节基因转录。在这里，使用成年小鼠皮层中的靶标切割和核酸酶测定下的释放，我们表明 MeCP2 与我们称为 MeCP2 结合热点 （MBH） 的特定基因增强子强烈结合。出乎意料的是，我们发现 MeCP2 与 MBHs 的结合在 MBHs 上以 DNA 甲基化非依赖性方式发生。基因周围的多个 MBH 位点介导富含神经元功能的基因的转录抑制。我们表明，MBHs 调节基因，而不管基因甲基化水平如何，这表明 MeCP2 通过基因内甲基化非依赖性机制控制转录。因此，MeCP2 对基因内甲基化非依赖性基因调控的破坏可能部分是 Rett 综合征的基础。