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

Mathies, Laura D.; Blackwell, GinaMari G.; Austin, Makeda K.; Edwards, Alexis C.; Riley, Brien P.; Davies, Andrew G.; Bettinger, Jill C.

doi:10.1073/pnas.1413451112

Cited by 34 publications

(59 citation statements)

References 52 publications

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“…This chromatin remodeling causes a reduction in expression of NPY in the amygdala which fits with enhanced anxiety during alcohol withdrawal (Pandey et al, 2008). In addition, the SWI/SWF chromatin remodeling complex is required in adult neurons of C.elegans for acute alcohol tolerance and genetic variation in a member of this complex is associated with alcohol dependence in humans (Mathies et al, 2015). Interestingly, a recent study demonstrated that the sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope, suppressing the expression of monoamine oxide B (MAOB) in the nucleus accumbens (Tsai et al, 2015).…”

Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50–60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled “Alcoholism”.

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Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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“…Interestingly, at least two genes ( swsn-7 and swsn-9 ) coding for SWI/SNF complex members in worms are required for the proper development of functional alcohol tolerance (Mathies et al, 2015). Furthermore, variants in one human SWI/SNF complex gene ( BRD7 ) associated significantly with alcohol dependence in a human genomewide association study (Mathies et al, 2015). Our results suggest that JmjC-KDMs might participate in the regulation of alcohol behaviors by modulating transcription via the SWI/SNF complex.…”

Section: Discussionmentioning

confidence: 99%

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

Pinzón

Reed

Shalaby

et al. 2017

Alcoholism Clin & Exp Res

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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 knock down using RNA interference (RNAi). Results Four of the 13 JmjC genes (KDM3, lid, NO66 and HSPBAP1) showed reproducible ethanol-sensitivity phenotypes. Some of the phenotypes were observed across doses, e.g. the enhanced ethanol-sensitivity of KDM3KO and NO66KO, but others were dose-dependent, such as the reduced ethanol sensitivity of HSPBAP1KO, or the enhanced ethanol 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, knock down of lid in the nervous system recapitulated the lidk phenotype, as was observed for KDM3KO and NO66KO RNAi-mediated knock down. Conclusion Our study reveals that the Drosophila JmjC-domain histone demethylases Lid, KDM3, NO66, and HSPBAP1 are required for normal ethanol-induced sedation and tolerance. Three of three tested of those four 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.

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“…We found that PBAF functions in differentiated neurons for the development of AFT (Mathies et al, 2015). Importantly, variation in two human SWI/SNF complex genes, SMARCA2 and BRD7 , was associated with AD in the Irish Affected Sib Pair Study for Alcohol Dependence (IASPSAD) (Mathies et al, 2015). …”

Section: Introductionmentioning

confidence: 87%

“…We previously found that BAF and PBAF affect different components of the acute response to ethanol in the genetic model Caenorhabditis elegans (Mathies et al, 2015): BAF is required for normal initial sensitivity to ethanol, while PBAF is required for the development of acute functional tolerance to ethanol (AFT). We found that PBAF functions in differentiated neurons for the development of AFT (Mathies et al, 2015). Importantly, variation in two human SWI/SNF complex genes, SMARCA2 and BRD7 , was associated with AD in the Irish Affected Sib Pair Study for Alcohol Dependence (IASPSAD) (Mathies et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations

Mathies

Alıev

Davies

et al. 2017

Alcoholism Clin & Exp Res

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Background Testing for direct gene/SNP replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in two members of the SWI/SNF chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in two independent samples. Methods We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (1) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case/control sample and (2) antisocial behavior, hypothesized to be a genetically-related developmental precursor, in a younger population sample (Spit for Science). Results We found evidence for association of the SWI/SNF complex with AD in COGA (p=0.0435) and more general antisocial behavior in Spit for Science (p=0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, SMARCB1 and BCL11A. In the Spit for Science sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal. Conclusions We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems.

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

Cited by 34 publications

References 52 publications

Genetic studies of alcohol dependence in the context of the addiction cycle

Genetic studies of alcohol dependence in the context of the addiction cycle

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

Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations

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