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

Jorge H. Pinzo´n, Addison R. Reed, Nevine A. Shalaby, Michael Buszczak, Aylin R. Rodan, Adrian Rothenfluh

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 nai¨ve 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.

Original languageEnglish (US)
JournalAlcoholism: Clinical and Experimental Research
DOIs
StateAccepted/In press - 2017

Fingerprint

Histone Demethylases
Neurology
Nervous System
Drosophila
Genes
Alcohols
Phenotype
RNA
Methylation
RNA Interference
Transgenes
Histones
Chromatin
Ethanol
Chromatin Assembly and Disassembly
Homologous Recombination
Mutation

Keywords

  • Drosophila
  • Alcohol Use Disorders
  • Behavior
  • Genetics
  • Histone Demethylases

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

@article{7e51e546fe56452fbfff54a1004e4e47,
title = "Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System",
abstract = "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 nai¨ve 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.",
keywords = "Drosophila, Alcohol Use Disorders, Behavior, Genetics, Histone Demethylases",
author = "Pinzo´n, {Jorge H.} and Reed, {Addison R.} and Shalaby, {Nevine A.} and Michael Buszczak and Rodan, {Aylin R.} and Adrian Rothenfluh",
year = "2017",
doi = "10.1111/acer.13508",
language = "English (US)",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System

AU - Pinzo´n, Jorge H.

AU - Reed, Addison R.

AU - Shalaby, Nevine A.

AU - Buszczak, Michael

AU - Rodan, Aylin R.

AU - Rothenfluh, Adrian

PY - 2017

Y1 - 2017

N2 - 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 nai¨ve 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.

AB - 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 nai¨ve 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.

KW - Drosophila

KW - Alcohol Use Disorders

KW - Behavior

KW - Genetics

KW - Histone Demethylases

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U2 - 10.1111/acer.13508

DO - 10.1111/acer.13508

M3 - Article

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AN - SCOPUS:85033233843

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

ER -