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Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

  • Gabor Egervari
    Affiliations
    Department of Psychiatry, Friedman Brain Institute

    Fishberg Department of Neuroscience, Friedman Brain Institute
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  • Joseph Landry
    Affiliations
    Department of Psychiatry, Friedman Brain Institute

    Fishberg Department of Neuroscience, Friedman Brain Institute
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  • James Callens
    Affiliations
    Department of Psychiatry, Friedman Brain Institute

    Fishberg Department of Neuroscience, Friedman Brain Institute
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  • John F. Fullard
    Affiliations
    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
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  • Panos Roussos
    Affiliations
    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
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  • Eva Keller
    Affiliations
    Department of Forensic Medicine, Semmelweis University, Budapest, Hungary
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  • Yasmin L. Hurd
    Correspondence
    Address correspondence to Yasmin Hurd, Icahn School of Medicine at Mount Sinai, Department of Psychiatry, Friedman Brain Institute, 1470 Madison Avenue, New York, NY 10029; .
    Affiliations
    Department of Psychiatry, Friedman Brain Institute

    Fishberg Department of Neuroscience, Friedman Brain Institute
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Published:September 28, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.09.015

      Abstract

      Background

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

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