Alcohol-Induced Neuroadaptation Is Orchestrated by the Histone Acetyltransferase CBP

Ghezzi, Alfredo; Li, Xiaolei; Lew, Linda; Wijesekera, Thilini P.; Atkinson, Nigel S.

doi:10.3389/fnmol.2017.00103

Cited by 15 publications

(15 citation statements)

References 54 publications

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“…Both CREBBP and EP300 appear in our top 20 genes related to human alcohol problems and epigenetics (Table 1 ), strongly supporting our interest in cpb-1 . CBP homologs have well described roles in the nervous system response to alcohol in animal models [ 27 – 31 ], and CREBBP is associated with addiction in humans [ 32 ]. We reasoned that if SWI/SNF is regulating ethanol response behaviors in part through its regulation of cbp-1 , then disrupting function of cbp-1 itself should alter ethanol response behaviors.…”

Section: Resultsmentioning

confidence: 99%

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

et al. 2020

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Background SWI/SNF chromatin remodeling genes are required for normal acute responses to alcohol in C. elegans and are associated with alcohol use disorder in two human populations. In an effort to discover the downstream genes that are mediating this effect, we identified SWI/SNF-regulated genes in C. elegans. Results To identify SWI/SNF-regulated genes in adults, we compared mRNA expression in wild type and swsn-1(os22ts) worms under conditions that produce inactive swsn-1 in mature cells. To identify SWI/SNF-regulated genes in neurons, we compared gene expression in swsn-9(ok1354) null mutant worms that harbor a neuronal rescue or a control construct. RNA sequencing was performed to an average depth of 25 million reads per sample using 50-base, paired-end reads. We found that 6813 transcripts were significantly differentially expressed between swsn-1(os22ts) mutants and wild-type worms and 2412 transcripts were significantly differentially expressed between swsn-9(ok1354) mutants and swsn-9(ok1354) mutants with neuronal rescue. We examined the intersection between these two datasets and identified 603 genes that were differentially expressed in the same direction in both comparisons; we defined these as SWI/SNF-regulated genes in neurons and in adults. Among the differentially expressed genes was cbp-1, a C. elegans homolog of the mammalian CBP/p300 family of histone acetyltransferases. CBP has been implicated in the epigenetic regulation in response to alcohol in animal models and a polymorphism in the human CBP gene, CREBBP, has been associated with alcohol-related phenotypes. We found that cbp-1 is required for the development of acute functional tolerance to alcohol in C. elegans. Conclusions We identified 603 transcripts that were regulated by two different SWI/SNF complex subunits in adults and in neurons. The SWI/SNF-regulated genes were highly enriched for genes involved in membrane rafts, suggesting an important role for this membrane microdomain in the acute alcohol response. Among the differentially expressed genes was cbp-1; CBP-1 homologs have been implicated in alcohol responses across phyla and we found that C. elegans cbp-1 was required for the acute alcohol response in worms.

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Section: Resultsmentioning

confidence: 99%

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

et al. 2020

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“…In the past 2 years, 3 alcohol studies from different Drosophila groups have identified a set of histone-modifying enzymes with direct roles in controlling adaptive alcohol responses. 60 – 62 These findings, reviewed below, have strengthened the link between epigenetic modifications and alcohol-induced neuroadaptations and have solidified the importance of the Drosophila model in elucidating the mechanisms of alcohol addiction.…”

Section: Drosophila Paves the Waymentioning

confidence: 90%

“…76 In Drosophila, CBP is encoded by the gene nej and it was recently linked to the development of functional alcohol tolerance. 61,77 In this article, Ghezzi and colleagues first showed that a mutation in nej significantly reduces tolerance to alcohol sedation. Moreover, when nej was artificially induced using a heat-inducible transgene, the experimenters were able to induce an increase in alcohol resistance that resembled the wild-type tolerance phenotype.…”

Section: The Histone Acetyltransferase Creb-binding Proteinmentioning

confidence: 99%

Epigenetic Mechanisms of Alcohol Neuroadaptation: Insights fromDrosophila

2018

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Alcohol addiction is a serious condition perpetuated by enduring physiological and behavioral adaptations. An important component of these adaptations is the long-term rearrangement of neuronal gene expression in the brain of the addicted individual. Epigenetic histone modifications have recently surfaced as important modulators of the transcriptional adaptation to alcohol as these are thought to represent a form of transcriptional memory that is directly imprinted on the chromosome. Some histone modifications affect transcription by modulating the accessibility of the underlying DNA, whereas others have been proposed to serve as marks read by transcription factors as a “histone code” that helps to specify the expression level of a gene. Although the effects of some epigenetic modifications on the transcriptional activity of genes are well known, the mechanisms by which alcohol consumption produces this rearrangement and leads to lasting changes in behavior remain unresolved. Recent advances using the Drosophila model system have started to unravel the epigenetic modulators underlying functional alcohol neuroadaptations. In this review, we discuss the role of 3 different histone modification systems in Drosophila, which have a direct impact on key alcohol neuroadaptations associated with the addictive process. These systems involve the histone deacetylase Sirt1, the histone acetyltransferase CREB-binding protein (CBP), and a subset of the Drosophila JmjC-Domain histone demethylase family.

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“…Tests of similar learning and memory genes revealed additional notable alcohol phenotypes caused by manipulations of rutabaga (rut) [11,142,197,198], encoding fly adenylyl cyclase, and dnc [193,199,200]. Separate from these pathways and studies, other studies have suggested alcohol-related roles of other genes in the network, including the cAMP-dependent protein kinase A (PKA) [114,197,201], protein kinase C (PKC) [79,[202][203][204], CREB [205][206][207], and CREB binding protein (CBP) [117,208], consistently suggesting a causal role of cAMP signaling pathways in alcohol abuse. The K + channel KCNQ is another example of the one-gene-at-a-time approach and the phenomenon of fly and human studies autonomously arriving at corroborating conclusions.…”

Section: Behavioral Screens In Drosophilamentioning

confidence: 99%

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

Lathen

Merrill

Rothenfluh

2020

IJMS

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Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

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Alcohol-Induced Neuroadaptation Is Orchestrated by the Histone Acetyltransferase CBP

Cited by 15 publications

References 54 publications

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

Epigenetic Mechanisms of Alcohol Neuroadaptation: Insights fromDrosophila

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

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