3 years ago

Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System

Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System
Michael Buszczak, Jorge H. Pinzón, Adrian Rothenfluh, Nevine A. Shalaby, Addison R. Reed, Aylin R. Rodan
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 AUDs. 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 (RNAi). Results Four of the 13 JmjC genes (KDM3, lid, NO66, and HSPBAP1) showed reproducible ethanol (EtOH) sensitivity phenotypes. Some of the phenotypes were observed across doses, for example, the enhanced EtOH sensitivity of KDM3KO and NO66KO, but others were dose dependent, such as the reduced EtOH sensitivity of HSPBAP1KO, or the enhanced EtOH tolerance of NO66KO. These phenotypes were rescued by their respective genomic transgenes in KDM3KO and NO66KO mutants. While we were unable to rescue lidk mutants, knockdown of lid in the nervous system recapitulated the lidk phenotype, as was observed for KDM3KO and NO66KO RNAi-mediated knockdown. Conclusions Our study reveals that the Drosophila JmjC-domain histone demethylases Lid, KDM3, NO66, and HSPBAP1 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. Alcohol use disorders are accompanied by long-lasting transcriptional changes. Often, these changes are regulated by histone modification, including methylation. A comprehensive survey of all JmjC-domain histone demethylases in Drosophila reveals that a subset of them affect alcohol-induced sedation and rapid tolerance. Furthermore, the ones investigated are required in the nervous system for normal responses to ethanol. Select JmjC-domain histone demethylases are, therefore, participating in the regulation of ethanol-induced behaviors and plasticity.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/acer.13508

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.