Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance

Abstract

Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol.

Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine

“…This suggests an interaction between alcohol-mediated DNA methylation and chromatin remodeling. In addition to methylation changes on the histone, genome wide histone acetylation is increased following alcohol administration (Ghezzi et al, 2013). In a rat model of alcohol addiction, decreased histone deacetylase (HDAC) activity and an increase in the acetylation of histones H3 and H4 is found in the amygdala (Pandey et al, 2008).…”

The Epigenetic Landscape of Alcoholism

“…A similar approach has been used in Drosophila to construct a gene network based on genome-wide histone H4 acetylation fold changes that occur at genomic loci following exposure to two drugs, benzyl alcohol and ethanol, utilizing the fact that these drugs produce mutual cross-tolerance. Among the 144 shared candidates discovered, the top gene clusters based on gene ontology belonged to the categories of transcriptional regulation, ion channels and synaptic plasticity genes (Ghezzi et al, 2013). Next-generation sequencing approaches have been used to determine global methylation levels in human post-mortem brains of alcoholics.…”

“…Drosophila CREB activates expression of the BK-type Ca2+ activated K channel gene ( dslo ) by binding to the promoter in response to benzyl alcohol sedation leading to a behavioral tolerance to the drug on a subsequent exposure (Wang, Ghezzi, et al, 2009). Furthermore, a mutation in the Drosophila homolog of CBP, nejire ( nej ), regulates tolerance to benzyl alcohol and ethanol (Ghezzi et al, 2013). Invertebrate models, such as Drosophila, have been invaluable in identifying genetic networks and pathways that regulate disease phenotypes that are conserved between invertebrate and mammalian models due to their forward and reverse genetic approaches (Atkinson, 2009).…”

Genetic architecture of natural variation in visual senescence in Drosophila

“…Drosophila melanogaster has emerged as a powerful genetic model system for the study of complex human disorders (15) including Alzheimer's disease (16), Parkinson's disease (17), Huntington's disease (18), ocular hypertension (6), retinal degeneration (7), longevity (19), sleep patterns (20), aggressive behaviors (21)(22)(23)(24), and sensitivity to alcohol (25)(26)(27)(28)(29)(30). Natural populations of Drosophila harbor substantial genetic variation for quantitative traits (31)(32)(33)(34).…”