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Alcohol‐Induced Behaviors Require a Subset of Drosophila JmjC‐Domain Histone Demethylases in the Nervous System
Author(s) -
Pinzón Jorge H.,
Reed Addison R.,
Shalaby Nevine A.,
Buszczak Michael,
Rodan Aylin R.,
Rothenfluh Adrian
Publication year - 2017
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13508
Subject(s) - drosophila (subgenus) , histone , biology , genetics , nervous system , domain (mathematical analysis) , drosophila melanogaster , evolutionary biology , neuroscience , gene , mathematics , mathematical analysis
Background Long‐lasting transcriptional changes underlie a number of adaptations that contribute to alcohol use disorders ( AUD ). Chromatin remodeling, including histone methylation, can confer distinct, long‐lasting transcriptional changes, and histone methylases are known to play a role in the development of addiction. Conversely, little is known about the relevance of Jumonji (JmjC) domain‐containing demethylases in AUD s. We systematically surveyed the alcohol‐induced phenotypes of null mutations in all 13 Drosophila JmjC genes. Methods We used a collection of JmjC mutants, the majority of which we generated by homologous recombination, and assayed them in the Booze‐o‐mat to determine their naïve sensitivity to sedation and their tolerance (change in sensitivity upon repeat exposure). Mutants with reproducible phenotypes had their phenotypes rescued with tagged genomic transgenes, and/or phenocopied by nervous system‐specific knockdown using RNA interference ( RNA i). Results Four of the 13 JmjC genes ( KDM 3 , lid , NO 66, and HSPBAP 1 ) showed reproducible ethanol (EtOH) sensitivity phenotypes. Some of the phenotypes were observed across doses, for example, the enhanced EtOH sensitivity of KDM 3 KO and NO 66 KO , but others were dose dependent, such as the reduced EtOH sensitivity of HSPBAP 1 KO , or the enhanced EtOH tolerance of NO 66 KO . These phenotypes were rescued by their respective genomic transgenes in KDM 3 KO and NO 66 KO mutants. While we were unable to rescue lid k mutants, knockdown of lid in the nervous system recapitulated the lid k phenotype, as was observed for KDM 3 KO and NO 66 KO RNA i‐mediated knockdown. Conclusions Our study reveals that the Drosophila JmjC‐domain histone demethylases Lid, KDM 3, NO 66, and HSPBAP 1 are required for normal EtOH‐induced sedation and tolerance. Three of 3 tested of those 4 JmjC genes are required in the nervous system for normal alcohol‐induced behavioral responses, suggesting that this gene family is an intriguing avenue for future research.