Exploration of alcohol use disorder-associated brain miRNA–mRNA regulatory networks

Abstract

Transcriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA–mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA–mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA–mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA–mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA–mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA–mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA–mRNA regulatory networks might contribute to AUD development.

RNA m6A Modification Changes in Postmortem Nucleus Accumbens of Subjects with Alcohol Use Disorder: A Pilot Study

“…Alcohol may enhance the expression of neuroinflammatory-related genes through epigenetic mechanisms such as RNA methylation. To understand whether the expression of the above 29 differentially methylated mRNAs was also significantly altered in postmortem NAc of AUD subjects, we re-analyzed our RNA-seq data [ 26 ] by comparing mRNA transcriptome profiles of six male Caucasian AUD subjects and six male Caucasian male control subjects (including the 3 male cases and the 3 male controls for the present study). However, we did not observe significant expression changes of the above 29 differentially methylated mRNAs at the level of expression fold changes over two and p values less than 0.05.…”

“…To identify alcohol-responsive genes expressed in the NAc, Flatscher-Bader et al performed cDNA microarray analysis of the transcriptome in postmortem NAc and found that alcohol-responsive genes were associated with vesicle formation and regulation of cell architecture, suggesting a neuroadaptation to chronic alcohol exposure at the level of synaptic structure and function [ 25 ]. In our recent study with the use of RNA sequencing (RNA-seq) to profile mRNA and microRNA (miRNA) transcriptomic changes in postmortem NAc of AUD subjects, we unraveled AUD-associated mRNA-miRNA pairs and their potentially influenced pathways (such as the CREB signaling in neurons) [ 26 ]. Recently, Drake et al assessed the role of long-noncoding RNA (lncRNAs) in postmortem NAc of AUD subjects [ 27 ].…”

Non-Invasive microRNA Profiling in Saliva can Serve as a Biomarker of Alcohol Exposure and Its Effects in Humans

“…( Gilad et al, 2008 ; Yang et al, 2018 ). It is tempting to consider microRNAs as an attractive alternative to traditional markers of alcohol consumption in AUD ( Rosato et al, 2019 ; Lim et al, 2021 ).…”

Functional roles, regulatory mechanisms and theranostics applications of ncRNAs in alcohol use disorder

“…Small RNA-seq analysis determined 19 mature DEmiRNAs (miR-10a-5p, miR-182-5p, miR-1246, miR-126b-5p, miR-4485-3p, miR-486-3p, miR-486-5p, miR-144-5p, miR-1248, miR-5100, miR-1231, miR-144-3p, miR-122-5p, miR-412-5p, miR-4326, miR-302a-5p, miR-6868-3p, miR-5196-3p and miR-412-5p) and 97 DEmRNAs in reward-related or alcohol-responsive brain regions of AUD subjects and controls. It was then revealed that the miRNAs-mRNAs regulatory networks constructed using differential expression and negative correlation pairs could regulate AUD-related pathways, including CREB signaling, IL-8 signaling and axon guidance signaling, which might contribute to the onset and progression of AUD [70]. A transcriptome analysis by microarray-based assay revealed the differential expression of miR-130a in postmortem PFC of 23 AUD subjects and 23 matched controls.…”