SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Significance Alcohol abuse is a significant social problem for which the molecular etiology is poorly understood. One recognized component of the progression to abuse disorders is the development of alcohol tolerance, and recently epigenetic modification of gene expression has been implicated in tolerance. Here, we use Caenorhabditis elegans to show that the conserved switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex, which modifies the transcriptional status of target genes, is required in adults and neurons for the development of acute alcohol tolerance. We predicted that allelic variation in genes that modify tolerance phenotypes may modify abuse liability in humans, and we identified a significant association between variation in one member of the SWI/SNF complex and a diagnosis of alcohol dependence in a human genomewide association study. 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 remodelin