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

Nat Neurosci. 2014 Feb;17(2):215-22. doi: 10.1038/nn.3607. Epub 2013 Dec 22.


DNA methylation has 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 regions of low CpG density, depleted at protein-DNA interaction sites and anticorrelated with gene expression. Functionally, both methylated CpGs (mCpGs) and mCpHs can repress transcription in vitro and are recognized by methyl-CpG binding protein 2 (MeCP2) in neurons in vivo. Unlike most CpG methylation, CpH methylation is established de novo during neuronal maturation and requires DNA methyltransferase 3A (DNMT3A) for active maintenance in postmitotic neurons. These characteristics of CpH methylation suggest that a substantially expanded proportion of the neuronal genome is under cytosine methylation regulation and provide a new foundation for understanding the role of this key epigenetic modification in the nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / growth & development
  • Brain / metabolism*
  • Chromatin Immunoprecipitation
  • CpG Islands / physiology*
  • DNA Methylation / physiology*
  • Electrophoretic Mobility Shift Assay
  • Embryo, Mammalian
  • Epigenomics*
  • Gene Expression / genetics*
  • Genome
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • RNA, Messenger / metabolism


  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • RNA, Messenger

Associated data

  • GEO/GSE52331