Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (ChIP-Seq)

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 at genes are established 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 found within regions of high non-CG methylation that are defined by domains of chromatin folding. Rather than working directly at transcriptional start sites to regulate these genes, MeCP2 represses enhancer elements that are enriched for methylated cytosines occurring in the CA or CG context. Enhancers repressed by MeCP2 are found within genes that are upregulated upon loss of the protein, providing a regulatory logic for how disruption of MeCP2 can lead to wide-spread changes in gene expression. Hence, we have found that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain. Overall design: ChIP-seq from the brains of MeCP2 KO, OE, and WT mice