RGD Reference Report - Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target. - Rat Genome Database

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

Authors: Egervari, Gabor  Landry, Joseph  Callens, James  Fullard, John F  Roussos, Panos  Keller, Eva  Hurd, Yasmin L 
Citation: Egervari G, etal., Biol Psychiatry. 2017 Apr 1;81(7):585-594. doi: 10.1016/j.biopsych.2016.09.015. Epub 2016 Sep 28.
RGD ID: 405096665
Pubmed: PMID:27863698   (View Abstract at PubMed)
PMCID: PMC5346335   (View Article at PubMed Central)
DOI: DOI:10.1016/j.biopsych.2016.09.015   (Journal Full-text)


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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
heroin dependence  IEP 405096665mRNA:increased expression:ventral striatum (human)RGD 
heroin dependence  ISOGRIA1 (Homo sapiens)405096665; 405096665mRNA:increased expression:ventral striatum (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gria1  (glutamate ionotropic receptor AMPA type subunit 1)

Genes (Mus musculus)
Gria1  (glutamate receptor, ionotropic, AMPA1 (alpha 1))

Genes (Homo sapiens)
GRIA1  (glutamate ionotropic receptor AMPA type subunit 1)


Additional Information