Neuronal non-CG methylation is an essential target for MeCP2 function

DNA methylation is implicated in neuronal biology via the protein MeCP2, mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 corepressor complexes to methylated cytosine in the CG dinucleotide, but also to non-CG methylation, which is abundant specifically in neuronal genomes. To test the biological significance of its dual binding specificity, we replaced the MeCP2 DNA binding domain with an orthologous domain whose specificity is restricted to mCG motifs. Knock-in mice expressing the domain-swap protein displayed severe Rett syndrome-like phenotypes, demonstrating that interaction with sites of non-CG methylation, specifically the mCAC trinucleotide, is critical for normal brain function. The results support the notion that the delayed onset of Rett syndrome is due to the late accumulation of both mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2-null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of particular relevance to the Rett syndrome phenotype.