MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation

• Published in: Molecular cell 2020-01, Vol.77 (2), p.279-293.e8
• Main Authors: Clemens, Adam W., Wu, Dennis Y., Moore, J. Russell, Christian, Diana L., Zhao, Guoyan, Gabel, Harrison W.
• Format: Article
• Language: English
• Subjects: Animals; Brain - physiology; cerebral cortex; Chromosomes - genetics; DNA methylation; DNA Methylation - genetics; enhancer; Enhancer Elements, Genetic - genetics; Female; Gene Expression Regulation - genetics; Genome - genetics; Humans; MeCP2; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; non-CG methylation; Rats; Repressor Proteins - genetics; Rett syndrome; topologically associating domains; transcription
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2019.10.033

The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain. [Display omitted] •Chromatin-folding domains shape regions of enriched non-CG DNA methylation in neurons•MeCP2 represses transcription of genes in domains of enriched non-CG DNA methylation•MeCP2 represses enhancers containing a high density of methylated CA and CG sites•Intragenic enhancer dysregulation contributes to MeCP2 mutant gene expression changes Clemens and Wu et al. demonstrate that DNMT3A establishes non-CG DNA methylation across topologically associating domains in neurons, resulting in broad regions of high and low methylation. Within regions of enriched DNA methylation, MeCP2 represses the activity of enhancers, regulating promoter activation for genes controlled by these enhancers.