title: An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior.
abstract: Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.
authors.affiliation: Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.|Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yonwoo
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Hsieh
authors.affiliation: Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.|Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Angela M
authors.identifier: 0000-0002-5775-8774
authors.initials: AM
authors.lastname: Lee
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Radiology &Biomedical Imaging Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.|Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coman
authors.affiliation: Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.|Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Heath
authors.affiliation: Department of Radiology &Biomedical Imaging Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.|Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Biomedical Engineering, Yale University School of Applied Science &Engineering, New Haven, Connecticut, USA.
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
authors.affiliation: Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yann S
authors.initials: YS
authors.lastname: Mineur
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Bordey
authors.affiliation: Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.|Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marina R
authors.identifier: 0000-0002-4404-1280
authors.initials: MR
authors.lastname: Picciotto
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; D009538:Nicotine; D011495:Histone-Lysine N-Methyltransferase