title: Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain.
abstract: 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.
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] [5].
authors.forename: Junjie U
authors.identifier: 0000000188710055
authors.initials: JU
authors.lastname: Guo
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3].
authors.forename: Yijing
authors.initials: Y
authors.lastname: Su
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Shin
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xie
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Thuc
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Guoping
authors.identifier: 0000000152356410
authors.initials: G
authors.lastname: Fan
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Guo-li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian; D057890:Epigenomics; D015870:Gene Expression / Q000235:genetics*; D016678:Genome; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000090205:DNA Methyltransferase 3A