title: SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans.
abstract: Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Mathies
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: GinaMari G
authors.initials: GG
authors.lastname: Blackwell
authors.affiliation: Departments of Pharmacology and Toxicology.
authors.forename: Makeda K
authors.initials: MK
authors.lastname: Austin
authors.affiliation: Psychiatry, and.
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Edwards
authors.affiliation: Psychiatry, and Human and Molecular Genetics and Virginia Commonwealth University-Alcohol Research Center, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Brien P
authors.identifier: http://orcid.org/0000-0002-2408-8268
authors.initials: BP
authors.lastname: Riley
authors.affiliation: Departments of Pharmacology and Toxicology, Virginia Commonwealth University-Alcohol Research Center, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Davies
authors.affiliation: Departments of Pharmacology and Toxicology, Virginia Commonwealth University-Alcohol Research Center, Virginia Commonwealth University, Richmond, VA 23298 jcbettinger@vcu.edu.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Bettinger
mesh_terms: D000437:Alcoholism / Q000175:diagnosis / Q000503:physiopathology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity; D055106:Genome-Wide Association Study; D006801:Humans; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D000431:Ethanol
keywords: C. elegans; GWAS; SWI/SNF; alcohol; chromatin remodeling