Dataset Information

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure.

ABSTRACT: Alcohol use disorder (AUD) is a chronic mental illness in which patients often achieve protracted periods of abstinence prior to relapse. Epigenetic mechanisms may provide an explanation for the persisting gene expression changes that can be observed even after long periods of abstinence and may contribute to relapse. In this study, we examined two histone modifications, histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3), in the prefrontal cortex of Withdrawal Seizure Resistant (WSR) mice 21 days after 72 h of ethanol vapor exposure. These histone modifications were selected because they are associated with active promoters (H3K4me3) and repressed gene expression in a euchromatic environment (H3K27me3). We performed a genome-wide analysis to identify differences in H3K4me3 and H3K27me3 levels in post-ethanol exposure vs. control mice by ChIP-seq. We detected a global reduction in H3K4me3 peaks and increase in H3K27me3 peaks in post-ethanol exposure mice compared to controls, these changes are consistent with persistent reductions in gene expression. Pathway analysis of genes displaying changes in H3K4me3 and H3K27me3 revealed enrichment for genes involved in proteoglycan and calcium signaling pathways, respectively. Microarray analysis of 7,683 genes and qPCR analysis identified eight genes displaying concordant regulation of gene expression and H3K4me3/H3K27me3. We also compared changes in H3K4me3 and/or H3K27me3 from our study with changes in gene expression in response to ethanol from published literature and we found that the expression of 52% of the genes with altered H3K4me3 binding and 40% of genes with H3K27me3 differences are altered by ethanol exposure. The chromatin changes associated with the 21-day post-exposure period suggest that this period is a unique state in the addiction cycle that differs from ethanol intoxication and acute withdrawal. These results provide insights into the enduring effects of ethanol on proteoglycan and calcium signaling genes in the brain.

SUBMITTER: Gavin DP

PROVIDER: S-EPMC6125400 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure.

Gavin David P DP Hashimoto Joel G JG Lazar Nathan H NH Carbone Lucia L Crabbe John C JC Guizzetti Marina M

Frontiers in genetics 20180830

Alcohol use disorder (AUD) is a chronic mental illness in which patients often achieve protracted periods of abstinence prior to relapse. Epigenetic mechanisms may provide an explanation for the persisting gene expression changes that can be observed even after long periods of abstinence and may contribute to relapse. In this study, we examined two histone modifications, histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3), in the prefrontal cortex of W ...[more]

PMID: 30214456

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Project description:Alcohol use disorder (AUD) is a chronic mental illness in which patients often achieve protracted periods of abstinence prior to relapse. Epigenetic mechanisms may provide an explanation for the persisting gene expression changes that can be observed even after long periods of abstinence and may contribute to relapse. In this study we examined two stable histone modifications, histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3), in the prefrontal cortex of Withdrawal Seizure Resistant (WSR) mice 21 days after 72 hours of ethanol vapor exposure. These histone modifications were selected because they are associated with active promoters (H3K4me3) and repressed gene expression in a euchromatic environment (H3K27me3). We performed a genome-wide analysis to identify differences in H3K4me3 and H3K27me3 levels in post-ethanol exposure vs. control mice by ChIP-seq. We detected a global reduction in H3K4me3 peaks and increase in H3K27me3 peaks in post-ethanol exposure mice compared to controls, these changes are consistent with persistent reductions in gene expression and suggest differential epigenetic regulation of genes during this post-exposure period. We also examined the correspondence between genes that displayed changes in H3K4me3 and/or H3K27me3 and were differentially expressed. The expression of 52% of the genes with altered H3K4me3 binding and 40% of genes with H3K27me3 differences found here is altered by ethanol exposure based on analysis of prior studies. Finally, pathway analysis of genes displaying changes in H3K4me3 and H3K27me3 revealed enrichment for genes involved in proteoglycan and calcium signaling pathways, respectively. The chromatin changes associated with the 21-day post-exposure period suggest that this period is a unique state in the addiction cycle that differs from ethanol intoxication and acute withdrawal. These results provide insights into the enduring effects of ethanol on proteoglycan and calcium signaling genes in the brain.

Project description:Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in non-synaptic proteins suggests that AIE may prime this signaling pathway for future ethanol exposures in adulthood.

Project description:Individuals with post-traumatic stress disorder (PTSD) often use alcohol to cope with their distress. This aberrant use of alcohol often develops into alcohol use disorder (AUD) leading to high rates of PTSD-AUD co-occurrence. Individuals with comorbid PTSD-AUD have more intense alcohol cravings and increased relapse rates during withdrawal than those with AUD alone. Also, individuals with PTSD or AUD alone often show similar psychological behaviors, such as impulsivity and anhedonia. Extensive clinical studies on the behavioral effects of PTSD-AUD comorbidity, namely alcohol use, have been performed. However, these effects have not been well studied or mechanistically explored in animal models. Therefore, the present study evaluated the effects of traumatic stress comorbid with alcohol exposures on ethanol intake, impulsivity, and anhedonia in mice. Adult male C57Bl/6 mice were first exposed to either mouse single-prolonged stress (mSPS), an animal model that has been validated for characteristics akin to PTSD symptoms, or control conditions. Baseline two-bottle choice ethanol consumption and preference tests were conducted after a 7-day isolation period, as part of the mSPS exposure. Next, mice were exposed to air or chronic intermittent ethanol (CIE), a vapor-induced ethanol dependence and withdrawal model, for 4 weeks. Two-bottle choice ethanol drinking was used to measure dependence-induced ethanol consumption and preference during periods intervening CIE cycles. The novelty suppressed feeding (NSF) test was used to evaluate impulsivity and anhedonia behaviors 48 h after mSPS and/or repeated CIE exposure. Results showed that, compared to control conditions, mSPS did not affect baseline ethanol consumption and preference. However, mSPS-CIE mice increased Post-CIE ethanol consumption compared to Control-Air mice. Mice exposed to mSPS had a shorter latency to feed during the NSF, whereas CIE-exposed mice consumed less palatable food reward in their home cage after the NSF. These results demonstrate that mice exposed to both mSPS and CIE are more vulnerable to ethanol withdrawal effects, and those exposed to mSPS have increased impulsivity, while CIE exposure increases anhedonia. Future studies to examine the relationship between behavioral outcomes and the molecular mechanisms in the brain after PTSD-AUD are warranted.

Dataset Information

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure.

Publications

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure.

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