Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges.

Autor: Vornholt E; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.; Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Drake J; Department of Psychiatry and Behavioral Sciences, Texas A&M University, College Station, Texas, USA., Mamdani M; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA., McMichael G; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA., Taylor ZN; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA., Bacanu SA; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA., Miles MF; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.; VCU-Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA., Vladimirov VI; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.; Department of Physiology & Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.; School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.; Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: Addiction biology [Addict Biol] 2021 Nov; Vol. 26 (6), pp. e13071. Date of Electronic Publication: 2021 Jun 23.
DOI: 10.1111/adb.13071
Abstrakt: 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.
(© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)
Databáze: MEDLINE
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