title: Role of Tet1 and 5-hydroxymethylcytosine in cocaine action.
abstract: Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ningyi
authors.initials: N
authors.lastname: Shao
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Szulwach
authors.affiliation: 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Institut National de la Santé et de la Recherhe Médicale (INSERM) U1130, CNRS UMR8246, UPMC UM18, Neuroscience Paris Seine, Paris, France.
authors.forename: Vincent
authors.identifier: 000000028212751X
authors.initials: V
authors.lastname: Vialou
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Thuc
authors.initials: T
authors.lastname: Le
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Efrain
authors.initials: E
authors.lastname: Ribeiro
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Labonte
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Laitman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Estey
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Stockman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Institut National de la Santé et de la Recherhe Médicale (INSERM) U1130, CNRS UMR8246, UPMC UM18, Neuroscience Paris Seine, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Couroussé
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Mensah
authors.affiliation: The McGill Group for Suicide Studies, Douglas Hospital Research Centre, McGill University, Montreal, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Guo-li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Guoping
authors.identifier: 0000000152356410
authors.initials: G
authors.lastname: Fan
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Li
authors.identifier: 0000000251902851
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D003042:Cocaine