Chromatin-mediated alternative splicing regulates cocaine-reward behavior.
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
15 09 2021
15 09 2021
Historique:
received:
07
02
2020
revised:
14
06
2021
accepted:
10
08
2021
pubmed:
5
9
2021
medline:
6
10
2021
entrez:
4
9
2021
Statut:
ppublish
Résumé
Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.
Identifiants
pubmed: 34480866
pii: S0896-6273(21)00603-6
doi: 10.1016/j.neuron.2021.08.008
pmc: PMC8454057
mid: NIHMS1734501
pii:
doi:
Substances chimiques
Chromatin
0
Dopamine Uptake Inhibitors
0
Cocaine
I5Y540LHVR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2943-2966.e8Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008076
Pays : United States
Organisme : NIDA NIH HHS
ID : K01 DA039308
Pays : United States
Organisme : NIDA NIH HHS
ID : R36 DA050877
Pays : United States
Organisme : NIDA NIH HHS
ID : DP1 DA044250
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA028874
Pays : United States
Organisme : NIDA NIH HHS
ID : R00 DA045795
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA033641
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA015214
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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