Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways.
JMJD3
KDM6B
alcoholism
epigenetics
inflammation
nucleus accumbens
prefrontal cortex
Journal
Addiction biology
ISSN: 1369-1600
Titre abrégé: Addict Biol
Pays: United States
ID NLM: 9604935
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
19
12
2018
revised:
28
05
2019
accepted:
09
07
2019
pubmed:
3
8
2019
medline:
10
9
2021
entrez:
3
8
2019
Statut:
ppublish
Résumé
Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could underlie transcriptomic and behavioral hallmarks of alcohol addiction. In the present study, we sought to identify epigenetic enzymes in the brain that are dysregulated during protracted abstinence as a consequence of chronic and intermittent alcohol exposure. Through quantitative mRNA expression analysis of over 100 epigenetic enzymes, we identified 11 that are significantly altered in alcohol-dependent rats compared with controls. Follow-up studies of one of these enzymes, the histone demethylase KDM6B, showed that this enzyme exhibits region-specific dysregulation in the prefrontal cortex and nucleus accumbens of alcohol-dependent rats. KDM6B was also upregulated in the human alcoholic brain. Upregulation of KDM6B protein in alcohol-dependent rats was accompanied by a decrease of trimethylation levels at histone H3, lysine 27 (H3K27me3), consistent with the known demethylase specificity of KDM6B. Subsequent epigenetic (chromatin immunoprecipitation [ChIP]-sequencing) analysis showed that alcohol-induced changes in H3K27me3 were significantly enriched at genes in the IL-6 signaling pathway, consistent with the well-characterized role of KDM6B in modulation of inflammatory responses. Knockdown of KDM6B in cultured microglial cells diminished IL-6 induction in response to an inflammatory stimulus. Our findings implicate a novel KDM6B-mediated epigenetic signaling pathway integrated with inflammatory signaling pathways that are known to underlie the development of alcohol addiction.
Identifiants
pubmed: 31373129
doi: 10.1111/adb.12816
pmc: PMC7757263
doi:
Substances chimiques
Histones
0
Ethanol
3K9958V90M
Histone Demethylases
EC 1.14.11.-
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM6B protein, human
EC 1.14.11.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12816Subventions
Organisme : NIDA NIH HHS
ID : R21 DA035592
Pays : United States
Organisme : NIAAA NIH HHS
ID : R28 AA012725
Pays : United States
Organisme : NINDS NIH HHS
ID : P50 NS071674
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA023781
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH084880
Pays : United States
Informations de copyright
© 2019 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
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