Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges.
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ABSTRACT:
PROVIDER: PRJNA722278 | ENA |
REPOSITORIES: ENA
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Project description:Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular-RNA (circRNA) are noncoding RNA that form closed-looped structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in nucleus accumbens (NAc) from 32 AD matched cases/controls. Significant circRNA (unadj. p≤0.05) were identified via regression and clustered in circRNA networks via WGCNA. CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. MatrixeQTL was used to identify eQTLs affecting circRNA expression. Genomic enrichment was used to detect overlap between eQTLs and recent GWAS of substance abuse. Significant circRNAs (N=542) clustered in 9 significant AD modules (FWER p≤0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA:miRNA:mRNA interactions (FDR≤0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we identified 96 significant circRNA eQTLs (unadj. p≤0.002), showing significant enrichment within recent alcohol use disorder (AUD) and smoking GWAS. To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNA impact mRNA expression by interacting with miRNA in the NAc of AD subjects. We further identify genetic variants affecting circRNA expression impacting potential miRNA and mRNA interactions. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.
2021-04-16 | GSE172166 | GEO
Project description:Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA-miRNA-mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.
| S-EPMC8590811 | biostudies-literature
Project description:Dried polyvinyl alcohol (PVA) sponges were used for subcutaneous implantation in the mice dorsum, and were harvested on days 3, 5, 10, and 16 post-implantation.
2024-06-30 | GSE261285 | GEO
Project description:The National Institute on Alcohol Abuse and Alcoholism has estimated that approximately 14 million people in the United States suffer from alcoholism. Alcohol sensitivity, the development of tolerance to alcohol and susceptibility to addiction vary in the population. Whereas environmental factors, such as stress and social experience, contribute to individual variation in sensitivity to chronic alcohol consumption, genetic factors have also been implicated. However, genetic polymorphisms that predispose to alcoholism remain largely unknown due to extensive genetic and environmental variation in human populations. Drosophila, however, allows studies on genetically identical individuals in controlled environments. Although addiction to alcohol has not been demonstrated in Drosophila, flies show responses to alcohol exposure that resemble human intoxication, including hyperactivity, loss of postural control, sedation, and exposure-dependent development of tolerance. We assessed whole-genome transcriptional responses following alcohol exposure and demonstrate immediate down-regulation of olfactory sensitivity and, concomitant with development of tolerance, altered transcription of enzymes associated with fatty acid biosynthesis. Our results identify key enzymes in conserved metabolic pathways that may contribute to human alcohol sensitivity. Keywords: Drosophila, model system, alcohol sensitivity, tolerance
2006-07-27 | GSE5382 | GEO
Project description:Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.
2020-04-07 | GSE137228 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNAs with strong biological functions. However, the roles of miRNAs in alcohol addiction are still unclear. In this study, we analyzed miRNA profile of in the nucleus accumbens (NAc) of rats treated with alcohol. The results demonstrated, among the 300 detected miRNAs in NAc, multiple miRNAs were aberrantly expressed after treatment with alcohol.
2013-08-01 | GSE47943 | GEO
Project description:Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown but interactions between these drugs have important implications for the development of, and recovery from drug dependence. Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the two behaviours on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by two-way ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Results: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from non alcoholics with the exception of one control case. All smokers were distinguished from non smokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism and signalling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodelling, proliferation and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway ‘regulation of the actin cytoskeleton’ was induced in response to alcohol and tobacco co-abuse and included. Conclusions: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system. The data set contained individual RNA samples extracted from the nucleus accumbens from 5 non smoking non drinking control case, 5 non smoking alcoholics, 5 non drinking smokers, and 5 smoking alcoholics. An aliquot if each sample was combined to generate a reference pool. Each sample was amplified individually and labelled with Cy3 in the process, the reference samples was amplified and labelled with Cy5. Each sample was hybridised competitively against the reference sample to 1 array.
2010-07-01 | E-GEOD-20568 | biostudies-arrayexpress
Project description:Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown but interactions between these drugs have important implications for the development of, and recovery from drug dependence. Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the two behaviours on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by two-way ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Results: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from non alcoholics with the exception of one control case. All smokers were distinguished from non smokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism and signalling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodelling, proliferation and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway ‘regulation of the actin cytoskeleton’ was induced in response to alcohol and tobacco co-abuse and included. Conclusions: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system.
2010-07-01 | GSE20568 | GEO
Project description:Background and Purpose: Alcohol use disorder (AUD) is a serious public health issue and affects the lives of numerous people. Previous studies have shown a link between nicotinic acetylcholine receptors (nAChR) and alcohol addiction. However, the role of α6β2* nAChR in alcohol addiction remains obscure and whether α6β2* nAChR can be used as a potential drug target for alcohol withdrawal need to be studied. Methods: Zebrafish (Danio rerio) were exposed to 0.2% alcohol for 14 days followed by 7 days of repeated withdrawal and then retro-orbitally injected with α-conotoxin TxIB (a selective α6β2* nAChR antagonist). RNA-sequencing (RNA-seq) and subsequent bioinformatics analysis were applied to explore the potential network regulation by blocking α6β2* nAChR using TxIB after alcohol withdrawal. Results: RNA sequencing of zebrafish brain indicated a total of 657 genes showed aberrant expression and among which 225 were reversed after TxIB injection. These reversed genes were significantly enriched in cardiac muscle contraction and calcium signaling pathways and the gene expression profile was further validated by RT-PCR. Conclusion: Our finding suggests α6β2* nAChR antagonists have the potential to modulate alcohol withdrawal.
2021-11-03 | GSE186926 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNAs with strong biological functions. However, the roles of miRNAs in alcohol addiction are still unclear. In this study, we analyzed miRNA profile of in the nucleus accumbens (NAc) of rats treated with alcohol. The results demonstrated, among the 300 detected miRNAs in NAc, multiple miRNAs were aberrantly expressed after treatment with alcohol. To perform the experiment, 18 male rats (weighing 150-180 g) were divided into two treatment groups: vehicle (500 ul saline, ip bid) or alcohol (1 g/kg, ip bid). Seven days later, the animals were sacrificed and their NAc were isolated for miRNA microarray analysis. The miRNA expressions were determined using miRNA microarrays for rat (LC Sciences). Data were normalized using cyclic method and statistically analyzed using Ttest.
2013-08-01 | E-GEOD-47943 | biostudies-arrayexpress