华盛顿大学医学院Harrison W. Gabel团队近日取得一项新成果。经过不懈努力，他们研制了MeCP2和非CG DNA甲基化稳定了区分密切相关神经元类型的长基因的表达。该研究于2025年5月12日发表于国际一流学术期刊《自然—神经科学》杂志上。

该研究组通过基因组和空间转录组分析表明，MeCP2在密切相关的神经元类型中保持转录组多样性。课题组人员根据全球mCA水平和解剖甲基化模式揭示了神经元群体对MeCP2缺失的差异易感性，这些模式驱动了共享和独特的MeCP2基因调控。研究组发现MeCP2调节长，mCA富集，“反复调谐”的基因，即在许多密切相关的神经元类型之间差异表达的基因，包括视觉皮层中跨空间不同的视觉依赖基因程序。因此，MeCP2维持神经元类型特异性基因程序以促进大脑细胞多样性。

研究人员表示，哺乳动物神经元的多样性是通过微妙的基因表达差异来描述的，这种差异可能需要特殊的机制来维持。神经元独特地表达基因组中最长的基因，并以非CG DNA甲基化（mCA）为主题，与Rett综合征蛋白甲基化-CpG结合蛋白2 （MeCP2）一起控制基因表达。然而，这些独特的基因结构和分子机制是否调节神经元多样性仍未被探索。

附：英文原文

Title: MeCP2 and non-CG DNA methylation stabilize the expression of long genes that distinguish closely related neuron types

Author: Moore, J. Russell, Nemera, Mati T., DSouza, Rinaldo D., Hamagami, Nicole, Clemens, Adam W., Beard, Diana C., Urman, Alaina, Razia, Yasmin, Rodriguez Mendoza, Victoria, Law, Travis E., Edwards, John R., Gabel, Harrison W.

Issue&Volume: 2025-05-12

Abstract: The diversity of mammalian neurons is delineated by subtle gene expression differences that may require specialized mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and use non-CG DNA methylation (mCA), together with the Rett syndrome protein methyl-CpG-binding protein 2 (MeCP2), to control gene expression. However, whether these distinctive gene structures and molecular machinery regulate neuronal diversity remains unexplored. Here, we use genomic and spatial transcriptomic analyses to show that MeCP2 maintains transcriptomic diversity across closely related neuron types. We uncover differential susceptibility of neuronal populations to MeCP2 loss according to global mCA levels and dissect methylation patterns driving shared and distinct MeCP2 gene regulation. We show that MeCP2 regulates long, mCA-enriched, ‘repeatedly tuned’ genes, that is, genes differentially expressed between many closely related neuron types, including across spatially distinct, vision-dependent gene programs in the visual cortex. Thus, MeCP2 maintains neuron type-specific gene programs to facilitate cellular diversity in the brain.

DOI: 10.1038/s41593-025-01947-w

Source: https://www.nature.com/articles/s41593-025-01947-w