title: Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target.
abstract: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain.
  
  
  
  We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights.
  
  
  
  Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior.
  
  
  
  Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Fishberg Department of Neuroscience, Friedman Brain Institute.
authors.forename: Gabor
authors.initials: G
authors.lastname: Egervari
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Fishberg Department of Neuroscience, Friedman Brain Institute.
authors.forename: Joseph
authors.initials: J
authors.lastname: Landry
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Fishberg Department of Neuroscience, Friedman Brain Institute.
authors.forename: James
authors.initials: J
authors.lastname: Callens
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York.
authors.forename: John F
authors.initials: JF
authors.lastname: Fullard
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York; Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, New York.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Forensic Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Keller
authors.affiliation: Department of Psychiatry, Friedman Brain Institute; Fishberg Department of Neuroscience, Friedman Brain Institute. Electronic address: Yasmin.Hurd@mssm.edu.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
mesh_terms: D000107:Acetylation; D000818:Animals; D001381:Azepines / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D044127:Epigenesis, Genetic; D057890:Epigenomics; D020869:Gene Expression Profiling; D006556:Heroin Dependence / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D012646:Self Administration; D014230:Triazoles / Q000008:administration & dosage; D044465:White People
chemical_list: D001381:Azepines; D006657:Histones; D018091:Receptors, AMPA; D014230:Triazoles; C561695:(+)-JQ1 compound
keywords: Addiction; Epigenetics; Glutamate; Heroin; Histone acetylation; JQ1