Enduring Histone Methylation Changes at Proteoglycan Network Genes following Ethanol Exposure
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PROVIDER: PRJNA483750 | ENA |
REPOSITORIES: ENA
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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.
2018-08-01 | GSE117925 | GEO
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 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.
| S-EPMC6125400 | biostudies-literature
Project description:We aimed to determine the toxicogenomic impacts and the mechanisms involved in preimplantation embryonic survival following 0.2% ethanol exposure in porcine embryos. Gene expression changes were measured with a porcine embryo specific microarray and confirmed by RT-qPCR. Compared to control, ethanol exposure led to a 43% decrease in blastocyst rate and activated pathways associated with oxidative stress and nervous system damage, such as TP53 and TGF.
2016-12-23 | GSE92609 | GEO
Project description:Ethanol is a well-known teratogen. While this teratogenic potential is well-characterized clinically, the mechanisms through which ethanol exposure results in developmental defects remain unclear. Here we use the zebrafish model to elucidate eye-specific mechanisms that may underlie ethanol-mediated microphthalmia (reduced eye size), using time-series microarray analysis of gene expression of eye tissues of embryos exposed to 1.5% ethanol vs. untreated embryos. We identified 62 genes differentially expressed in ethanol-treated as compared to control zebrafish eyes from all sampling times over the period of retinal neurogenesis (24-48 hours post-fertilization). Application of the EDGE (extraction of differential gene expression) algorithm identified over 3000 genes differentially expressed over developmental time in ethanol-treated embryo eyes as compared to untreated embryo eyes. These lists included several genes indicating a mis-regulated cellular stress response (heat shock response) due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino (MO) targeting heat shock factor 1 (hsf-1) mRNA resulted in a microphthalmic phenotype, suggesting convergent molecular pathways. Manipulation of the heat shock response by thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. Together these data are consistent with roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure in zebrafish.
2014-01-01 | GSE51427 | GEO
Project description:Ethanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanol-dysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.
2020-02-20 | GSE145574 | GEO
Project description:For yeast cells, tolerance to high levels of ethanol is vital both in their natural environment and in industrially relevant conditions. We recently genotyped experimentally evolved yeast strains, tolerant to high levels of ethanol. In this study, we elucidate how the genotype and phenotype are related to each other on the molecular level through an integrated analysis of mutation data with protein abundance profiles from six evolved, ethanol-tolerant clones. We constructed a protein network of regulatory proteins, mutated and differentially regulated proteins. This resulted in the identification of a rewired regulatory network after adaptation to high levels of ethanol.
2020-12-03 | PXD006631 | Pride
Project description:Purpose: Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus. FASD occur in up to 1-5% of live births in the United States and there currently is no cure. Ethanol exposure to the developing central nervous system (CNS) has profound effects on learning and memory, impulse control, and motor function, resulting from neuropathology. The purpose of the current study was to perform transcriptome analysis to evaluate the effects of early postnatal ethanol exposure in the hippocampus and cerebellum. Methods: Postnatal C57BL/6 mice were treated with 4g/kg of ethanol from P4-P9, brains were harvested 24h after the final treatment at P10, hippocampi and cerebella were microdissected, RNA was isolated, and RNASeq analysis was performed. We compared differences in gene expression, sex-dependent expression, and global biological pathways associated with disruptions in hippocampal and cerebellar genes between the ethanol and vehicle treated neonates. Results: Ethanol caused both an up and down regulation of genes associated with the hippocampus and cerebellum, which may result in the disruption of normal circuitry and maturation and growth in these brain regions. Ethanol increased the expression of genes associated with the S phase of the cell cycle in both the hippocampus and cerebellum. In the cerebellum, ethanol increased effector gene expression, and in the hippocampus, genes associated with different interneuron lineages were altered. Postnatal ethanol exposure also resulted in altered expression of genes associated with oligodendrocyte lineages and myelination, along with alterations in microglia associated genes. Conclusion: Collectively, these data indicate that ethanol has profound effects on the hippocampus and cerebellum, resulting in alterations of gene expression and biological pathways regulating neurodevelopment. These studies may have important implications concerning alcohol-induced neuropathology and the neurological effects seen across the life span in FASD.
2021-08-04 | GSE166196 | GEO
Project description:Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila.
2009-12-15 | GSE18208 | GEO
Project description:Exposure to alcohol during early embryonic or fetal development has been linked with a variety of adverse outcomes, the most common of which are structural and functional abnormalities of the central nervous system. Behavioral and cognitive deficits reported in individuals exposed to alcohol in utero include intellectual impairment, learning and memory difficulties, diminished executive functioning, attention problems, poor motor function and hyperactivity. The economic and social costs of these outcomes are substantial and profound. Improvement of neurobehavioural outcomes following prenatal alcohol exposure requires greater understanding of the mechanisms of alcohol-induced damage to the brain. Here we use a mouse model of relatively moderate ethanol exposure early in pregnancy and profile gene expression in the hippocampus and caudate putamen of adult male offspring. The effects of offspring sex and age on ethanol-sensitive hippocampal gene expression were also examined.
2016-10-20 | GSE87703 | GEO
Project description:Exposure to alcohol during early embryonic or fetal development has been linked with a variety of adverse outcomes, the most common of which are structural and functional abnormalities of the central nervous system. Behavioral and cognitive deficits reported in individuals exposed to alcohol in utero include intellectual impairment, learning and memory difficulties, diminished executive functioning, attention problems, poor motor function and hyperactivity. The economic and social costs of these outcomes are substantial and profound. Improvement of neurobehavioural outcomes following prenatal alcohol exposure requires greater understanding of the mechanisms of alcohol-induced damage to the brain. Here we use a mouse model of relatively moderate ethanol exposure early in pregnancy and profile gene expression in the hippocampus and caudate putamen of adult male offspring. The effects of offspring sex and age on ethanol-sensitive hippocampal gene expression were also examined.
2016-10-20 | GSE87699 | GEO