DNA methylation associated with future risky ethanol use.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1245326 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32949200_1.fastq.gz | Fastqsanger.gz | |||
| SRR32949200_2.fastq.gz | Fastqsanger.gz | |||
| SRR32949201_1.fastq.gz | Fastqsanger.gz | |||
| SRR32949201_2.fastq.gz | Fastqsanger.gz | |||
| SRR32949191_1.fastq.gz | Fastqsanger.gz |
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Project description:Alcohol use disorder (AUD) is a highly prevalent, complex, multifactorial and heterogeneous disorder, with 11% and 30% of adults meeting criteria for past-year and lifetime AUD, respectively. Identification of the molecular mechanisms underlying risk for AUD would facilitate effective deployment of personalized interventions. Studies using rhesus monkeys and rats, have demonstrated that individuals with low cognitive flexibility and a predisposition towards habitual behaviors show an increased risk for future heavy drinking. Further, low cognitive flexibility is associated with reduced dorsolateral prefrontal cortex (dlPFC) function in rhesus monkeys. To explore the underlying unique molecular signatures that increase risk for chronic heavy drinking, a genome-wide DNA methylation (DNAm) analysis of the alcohol-naïve dlPFC-A46 biopsy prior to chronic alcohol self-administration was conducted. The DNAm profile provides a molecular snapshot of the alcohol-naïve dlPFC, with mapped genes and associated signaling pathways that vary across individuals. The analysis identified 1,463 differentially methylated regions (DMRs) related to unique genes that were strongly associated with average ethanol intake consumed over 6 months of voluntary self-administration. These findings translate behavioral phenotypes into neural markers of risk for AUD, and hold promise for parallel discoveries in risk for other disorders involving impaired cognitive flexibility.
2025-04-02 | GSE293587 | GEO
Project description:A study on the mechanisms of ethanol-use in a chain elongation process
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Project description:Despite recent extensive genomic and genetic studies on behavioral responses to ethanol, relatively few new therapeutic targets for the treatment of alcohol use disorder have been validated. Here we describe a cross-species genomic approach focused on identifying gene networks associated with chronic ethanol consumption. To identify brain mechanisms underlying a chronic ethanol consumption phenotype highly relevant to human alcohol use disorder, and to elucidate potential future therapeutic targets, we conducted a genomic study in a nonhuman primate model of chronic open-access ethanol consumption. Microarray analysis of RNA expression in anterior cingulate and subgenual cortices from rhesus macaques was performed across multiple cohorts of animals. Gene networks correlating with ethanol consumption or showing enrichment for ethanol-regulated genes were identified, as were major ethanol-related hub genes within these networks. A subsequent consensus module analysis was used to co-analyze monkey data with expression data from a chronic intermittent ethanol vapor-exposure and consumption model in C57BL/6J mice. Ethanol-related gene networks conserved between primates and rodents were enriched for genes involved discrete biological functions, including; myelination, synaptic transmission, chromatin modification, Golgi apparatus function, translation, cellular respiration, and RNA processing. The myelin-related network, in particular, showed strong correlations with ethanol consumption behavior and displayed marked network reorganization between control and ethanol-drinking animals. Further bioinformatics analysis revealed that these networks also showed highly significant overlap with other ethanol-regulated gene sets. Altogether, these studies provide robust primate and rodent cross-species validation of gene networks associated with chronic ethanol consumption. Our results also suggest potential novel focal points for future therapeutic interventions in alcohol use disorder.
2019-09-03 | GSE134546 | 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 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.
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Project description:This experiment is an application of MeDIP-seq on hippocampus in a mouse model of fetal alcohol spectrum disorder (FASD). Here, we investigate genome-wide changes in DNA methylation in six C57BL/6 mice (3 ethanol-exposed and 3 saline-exposed). Mice were injected with either ethanol or saline on postnatal days 4 and 7, with hippocampal DNA methylation assessed on postnatal day 21. Across the six mice, there are 151,911 MeDIP peaks mapped to “intergenic”, “gene body”, or “promoter” based on the DNAm peaks proximity to a gene. Of these locations, 18,992 regions (16,374 intergenic, 1,887 gene body, 661 promoter) were common in all six mice (113,532 total) and can be combined for further analysis.
2017-07-20 | GSE101636 | GEO
Project description:Alcohol use disorder (AUD) has a profound public health impact and understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Many genetic risk loci have been identified for AUD or alcohol consumption, though the neurobiological mechanisms underlying these loci remain largely unknown. DNA methylation (DNAm) differences between individuals with and without AUD can provide insight into the mechanisms that predispose to AUD and consequences of AUD itself. Here, we provide Illumina HumanMethylation EPIC array data generated in nucleus accumbens and dorsolateral prefrontal cortex, both addiction relevant brain tissues, from 119 decedents of European ancestry: 61 controls and 58 cases. From these data we have conducted an epigenome-wide association study (EWAS) and identified several CpG associations with AUD. A subset of the identified CpGs map to genes that were previoulsy identified as associated with substance use behaviors in genetic studies, but the other CpGs map to genes previoulsy unassociated with substance use behaviors and are novel.
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Project description:Fetal alcohol spectrum disorder (FASD) is a common developmental behavioral disorder caused by maternal drinking during pregnancy. Children born with FASD often face additional stress, particularly maternal separation that adds yet additional deficits. The mechanism associated with this phenomenon is not known. Using a mouse model, prenatal ethanol exposure and maternal separation stress have resulted in behavioral deficits and the combination of treatments results in more than additive effects. In addition, behavioral alterations are associated with changes in hippocampal gene expression that persist into adulthood. What initiates and maintains these changes remains to be established and forms the focus of this research. Specifically, MeDIP-Seq was used to assess how changes in promoter DNA methylation are affected by the combination of prenatal ethanol exposure and maternal separation stress with the potential to affect gene expression. The novel results show different sets of genes implicated by promoter DNA methylation affected by both treatments independently, and a relatively unique set of genes affected by the combination of treatments. Prenatal ethanol exposure leads to altered promoter DNA methylation at genes important for brain function and transcriptional regulation. Maternal separation stress leads to changes at genes important for histone methylation and immune response, and the combination of two treatments results in DNA methylation changes at genes important for neuronal migration and immune response. Our dual results on gene expression and DNA methylation from the same samples have allowed comparison of the two observations. There is minimal reciprocal overlap between changes in promoter DNA methylation and gene expression, although overlapping genes tend to be critical for brain development and function. These results suggest that epigenetic mechanisms beyond promoter DNA methylation must be involved in lasting gene expression alterations leading to behavioral deficits implicated in FASD.
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Project description:Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
2023-02-21 | GSE220745 | GEO
Project description:Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
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Project description:Glucocorticoid Exposure During Hippocampal Neurogenesis Primes Future Stress Response by Inducing Long-Lasting Changes in DNA Methylation [methylation]
| PRJNA490451 | ENA