The genomes of mammalian neurons are enriched for unique forms of DNA methylation, including exceptionally high levels of non-CG methylation. Here, we review recent studies defining how non-CG methylation accumulates in neurons and is read out by the critical regulator of neuronal transcription, MeCP2. We discuss the role of gene expression and genome architecture in establishing non-CG methylation and highlight emerging mechanistic insights into how non-CG methylation and MeCP2 control transcription. Further, we describe the cell type-specific functions of this methylation and explore growing evidence that disruption of this regulatory pathway contributes to neurodevelopmental disorders. These findings uncover how the distinctive epigenome in neurons facilitates the development and function of the complex mammalian brain.

哺乳动物神经元的基因组富含独特形式的 DNA 甲基化，包括异常高水平的非 CG 甲基化。在这里，我们回顾了最近的研究，这些研究定义了非 CG 甲基化如何在神经元中积累，并由神经元转录的关键调节因子 MeCP2 读出。我们讨论了基因表达和基因组结构在建立非 CG 甲基化中的作用，并强调了关于非 CG 甲基化和 MeCP2 如何控制转录的新兴机制见解。此外，我们描述了这种甲基化的细胞类型特异性功能，并探索了越来越多的证据表明这种调节途径的破坏会导致神经发育障碍。这些发现揭示了神经元中独特的表观基因组如何促进复杂的哺乳动物大脑的发育和功能。