Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(6), P. 2224 - 2237

Published: May 12, 2020

Alcohol use disorder (AUD) is a chronic debilitating with limited treatment options and poorly defined pathophysiology. There are substantial genetic epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for (total N = 625) employed top hit replication (N 4798) using cross-tissue/cross-phenotypic approach goal of identifying novel targets relevant AUD. Results show that network differentially methylated regions in glucocorticoid signaling inflammation-related genes were associated alcohol behaviors. A probe consistently across all cohorts was located long non-coding RNA growth arrest specific five gene (GAS5) (p < 10-24). GAS5 has been implicated regulating transcriptional activity receptor multiple functions related apoptosis, immune function various cancers. Endophenotypic peripheral cortisol levels neuroimaging paradigms showed methylomic variation network-related probes stress phenotypes. Postmortem brain documented increased expression amygdala individuals Our data suggest differential system might influence inflammatory reactivity subsequently risk

Language: Английский

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Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

Addiction Biology, Journal Year: 2021, Volume and Issue: 26(6)

Published: Feb. 3, 2021

Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there heritable component, the etiology of AUD complex can involve environmental exposures like trauma be associated with many different patterns alcohol consumption. Epigenetic modifications, which mediate influence genetic variants variables on gene expression, have emerged as an important area research. Over past decade, number studies investigating DNA methylation, form epigenetic modification, has grown rapidly. Yet we are still far from understanding how methylation contributes or reflects aspects AUD. In this paper, reviewed discussed field evolved. We found that global candidate did not produce replicable results. To assess whether findings epigenome-wide association (EWAS) were replicated, aggregated significant across identified 184 genes 15 ontological pathways differentially methylated in at least two four three studies. These repeatedly enrichment immune processes, line recent developments suggesting system may altered Finally, current limitations make recommendations design future resolve outstanding questions.

Language: Английский

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How alcohol drinking affects our genes: an epigenetic point of view

Biochemistry and Cell Biology, Journal Year: 2018, Volume and Issue: 97(4), P. 345 - 356

Published: Nov. 9, 2018

This work highlights recent studies in epigenetic mechanisms that play a role alcoholism, which is complex multifactorial disorder. There large body of evidence showing alcohol can modify gene expression through processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In regard, chronic exposure to ethanol modifies methylation, acetylation, microRNA expression. The alcohol-mediated chromatin the brain promotes transition from use abuse addiction. Unravelling multiplex pattern molecular modifications induced by could support development new therapies for alcoholism drug addiction targeting processes.

Language: Английский

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Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood

The International Journal of Neuropsychopharmacology, Journal Year: 2017, Volume and Issue: 20(9), P. 758 - 768

Published: May 31, 2017

Adolescent intermittent ethanol exposure causes long-lasting alterations in brain epigenetic mechanisms. Melanocortin and neuropeptide Y signaling interact are affected by the brain. Here, persistent effects of adolescent on alpha-melanocyte stimulating hormone, melanocortin 4 receptor, expression their regulation histone acetylation mechanisms were investigated adulthood. Male rats exposed to (2 g/kg, i.p.) or volume-matched saline from postnatal days 28 41 allowed grow day 92. Anxiety-like behaviors measured elevated plus-maze test. Brain regions adult used examine changes status promoters. ethanol-exposed displayed anxiety-like showed increased pro-opiomelanocortin mRNA levels hypothalamus receptor both amygdala compared with saline-exposed rats. The alpha-Melanocyte hormone protein central medial nucleus amygdala, paraventricular nucleus, arcuate Neuropeptide decreased Histone H3K9/14 was promoter but gene promoters controls. Increased activity due emotional circuitry may play a role ethanol-induced anxiety phenotypes

Language: Английский

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Regulation of GABAA Receptor Subunit Expression in Substance Use Disorders

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4445 - 4445

Published: June 22, 2020

The modulation of neuronal cell firing is mediated by the release neurotransmitter GABA (γ-aminobuytric acid), which binds to two major families receptors. ionotropic GABAA receptors (GABAARs) are composed five distinct subunits that vary in expression brain region and type. action on GABAARs modulated a variety clinically pharmacologically important drugs such as benzodiazepines alcohol. Exposure abuse these substances disrupts homeostasis induces plasticity GABAergic neurotransmission, often via regulation receptor expression. Here, we review GABAAR subunit adaptive pathological plasticity, with focus substance use. We examine factors influencing genes including 5′ 3′ untranslated regions, variations DNA methylation, immediate early transcription regulate expression, translational post-translational modifications, other forms beyond Advancing our understanding regulating during well use withdrawal will provide insight into role signaling disorders, contribute development novel targeted therapies.

Language: Английский

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Synthesis of tin dioxide (SnO2) hollow nanospheres and its ethanol-sensing performance augmented by gold nanoparticle decoration

Journal of Alloys and Compounds, Journal Year: 2021, Volume and Issue: 883, P. 160868 - 160868

Published: June 18, 2021

Language: Английский

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DNA methylation signatures: Biomarkers of drug and alcohol abuse

Mutation Research/Reviews in Mutation Research, Journal Year: 2018, Volume and Issue: 777, P. 19 - 28

Published: June 21, 2018

Language: Английский

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Emerging Role of One-Carbon Metabolism and DNA Methylation Enrichment on δ-Containing GABAA Receptor Expression in the Cerebellum of Subjects with Alcohol Use Disorders (AUD)

The International Journal of Neuropsychopharmacology, Journal Year: 2017, Volume and Issue: 20(12), P. 1013 - 1026

Published: Aug. 11, 2017

Cerebellum is an area of the brain particularly sensitive to effects acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α6/δ-containing GABAA receptors located on glutamatergic granule cells. Here, we studied whether consumption induces changes in receptor subunit expression these are associated with alterations epigenetic mechanisms via DNA methylation. We used a cohort postmortem cerebellum control alcoholics, here defined as use disorders subjects (n=25/group). S-adenosyl-methionine/S-adenosyl-homocysteine were measured high-performance liquid chromatography. mRNA levels various genes assessed reverse transcriptase-quantitative polymerase chain reaction. Promoter methylation enrichment was using methylated immunoprecipitation hydroxy-methylated assays. mRNAs encoding key enzymes 1-carbon metabolism that determine ratio increased, indicating higher "methylation index" disorder subjects. found increased promoter δ reduced protein No observed α1- or α6-containing subunits. The DNA-methyltransferases (1, 3A, 3B) unaltered, whereas level TET1, which participates demethylation pathway, decreased. Hence, may result alcohol-induced reduction demethylation. Together, results support hypothesis aberrant pathways be involved pathophysiology alcoholism. Furthermore, this work provides novel evidence for central role neuroadaptive human function.

Language: Английский

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Epigenome‐Wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption Among European American Male Veterans

Alcoholism Clinical and Experimental Research, Journal Year: 2019, Volume and Issue: 43(10), P. 2111 - 2121

Published: Aug. 6, 2019

Background Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations DNA methylation. Thus, methylation signatures peripheral cells provide biomarkers of the impact use and risk for future consumption. Method Using a high‐density array, we characterized epigenome‐wide saliva with respect to large cohort male European American veterans. In this study, over 870,000 CpG sites was profiled 1,135 men. Alcohol assessed using Use Disorder Identification Test‐Consumption ( AUDIT ‐C). Linear regression applied an association study EWAS ), adjusted confounders. Gene set enrichment analysis performed KEGG database correction gene length. Results We found that total 70 reached ‐corrected significance p < 6E‐08) small on individual sites, including 64 new 6 were previously reported as associated disorder, liver function, body mass index, lipid metabolism. The most site located SLC 7A11 t = −11.34, 2.66E‐28), involved specifically cysteine glutamate transportation. 44 genes, genes amino acid transport metabolism systems. identified 68 pathways false discovery rate 0.05. Conclusions novel shed light mechanisms health outcomes among heavy drinkers.

Language: Английский

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Non-coding RNA in alcohol use disorder by affecting synaptic plasticity

Experimental Brain Research, Journal Year: 2022, Volume and Issue: 240(2), P. 365 - 379

Published: Jan. 13, 2022

Language: Английский

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