MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome

• DOI: 10.1073/pnas.1505909112
• Publication Date: 2015-04-14T02:41:48Z
• Authors: Lin Chen; Kaifu Chen; Laura A. Lavery; Steven Andrew Baker; Chad A. Shaw; Wei Li; Huda Y. Zoghbi
• Keywords: Male; Neurons; 0301 basic medicine; Transcription, Genetic; Methyl-CpG-Binding Protein 2; Brain-Derived Neurotrophic Factor; Mice, Transgenic; DNA; DNA Methylation; Disease Models, Animal; Mice; 03 medical and health sciences; Gene Expression Regulation; Rett Syndrome; Animals

Significance Decades of research have not deciphered the mechanism by which methyl-CpG binding protein 2 (MeCP2) regulates transcription and why Rett symptoms manifest 1 to 2 y after birth. We hypothesized that the temporal dynamics of MeCP2 binding might provide an answer. We developed mice with an EGFP-tagged MeCP2 allele to identify high-resolution MeCP2 binding profiles in the adult mouse brain. Using genomic binding profiles, methylation maps, and mRNA deep-sequencing data, we found MeCP2 binds to non-CG methylation (mCH, not mCG) to regulate expression of genes altered in mouse models of MeCP2 disorders. These data and the parallel timing of mCH and MeCP2 postnatal accumulation suggest MeCP2 binds mCH as neurons mature to regulate gene expression, offering an explanation for the delayed onset of Rett.