title: Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.
abstract: Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Heller
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Cates
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Peña
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Haosheng
authors.initials: H
authors.lastname: Sun
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: 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: Sam A
authors.identifier: 0000000221042272
authors.initials: SA
authors.lastname: Golden
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.affiliation: 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazei-Robison
authors.affiliation: 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Sigma Aldrich, Saint Louis, Missouri, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Knight
authors.affiliation: Sigma Aldrich, Saint Louis, Missouri, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gerber
authors.affiliation: Sigma Aldrich, Saint Louis, Missouri, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Nievera
authors.affiliation: Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Tamminga
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
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: Sangamo Biosciences Inc., Richmond, California.
authors.forename: H Steve
authors.initials: HS
authors.lastname: Zhang
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
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: D000328:Adult; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003863:Depression / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009714:Nucleus Accumbens / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*
chemical_list: C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos