Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain

Abstract

DNA methylation plays critical roles in the nervous system and has been traditionally considered to be restricted to CpG dinucleotides in metazoan genomes. Here we show that the single-base resolution DNA methylome from adult mouse dentate neurons consists of both CpG (~75%) and CpH (~25%) methylation (H = A/C/T). Neuronal CpH methylation is conserved in human brains, enriched in low CpG-density regions, depleted at protein-DNA interaction sites, and anti-correlated with gene expression. Functionally, both mCpGs and mCpHs can repress transcription in vitro and are recognized by MeCP2 in neurons in vivo. Unlike most CpG methylation, CpH methylation is established de novo during neuronal maturation and requires DNMT3A for active maintenance in post-mitotic neurons. These characteristics of CpH methylation suggest a significantly expanded proportion of the neuronal genome under cytosine methylation regulation and provide a new foundation for understanding the role of this key epigenetic modification in the nervous system.

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

“…Additionally, ranking all genes by mRNA transcript abundance revealed an inverse relationship between DNA methylation and transcriptional activity (Fig. S5), consistent with previous observations (15,19).…”

“…Interestingly, nucleosome occupancy positively correlates with mCG levels (21), and recent data suggest that mCH is spaced similarly to nucleosomes (15,19). We mapped nucleosome positioning in adult mouse hypothalamus (Fig.…”

“…DNA methylation has been implicated in the regulation of gene expression (15,19,23,24). To explore how MeCP2 binding to methylated DNA is involved in transcriptional regulation, we performed transcriptional profiling (mRNA-Seq) in adult MeCP2-null, MeCP2-overexpressing, and wild-type mouse hypothalami.…”

“…Recent in vivo studies in the adult mouse brain confirm the preference of MeCP2 for mCG over nonmethylated CG, although MeCP2 clearly binds widely across the entire genome (11). Other studies have observed that MeCP2 binds to nonspecific DNA elements via its A/T hooks and basic and disordered protein domains, as well as to mCH, although the functional relevance of these interactions has not been explored (12)(13)(14)(15)(16). Given that MeCP2 levels rise in mammalian neurons for some time after birth (11,17) and approach those of the histone-octamer in the adult mouse brain (11), its differential binding to other DNA elements besides mCG is expected but has not yet been defined experimentally at high resolution.…”

In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas-Tragedy survivors

“…Global hypomethylation also results in genome wide instability that leads to oncogenesis (Guo et al, 2014). DNA Methyl Transferase (DNMT) is relatively large protein family that controls methylation and responsible for cell growth and its survival in mammals (Qin et al, 2011).…”