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

Abstract

Alcohol use disorder (AUD) is due to gene expression changes in specific brain regions, 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 postmortem 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 Caucasians. 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 postmortem tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control Caucasians, and some of the AUD-associated miRNA-mRNA regulatory networks were confirmed. Additionally, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with and 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.

Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons

“…5J.d-e). Ethanol has been found to affect microRNA expression patterns that regulate mRNA 49,[54][55][56][57][58][59] . It is intriguing to speculate that ethanol might increase expression of GIRK2 through this type of mechanism, with polymorphisms in the 3'UTR serving as the modulator.…”

microRNA-dependent regulation of gene expression in GABAergic interneurons

“…In this review, we assemble and arrange recent data regarding miRNA-dependent gene regulation of GABAergic IN activity, with the aim to shed light onto mechanisms by which miRNA-dependent control of gene expression in INs contributes to sculpting brain circuit dynamics. We propose that elucidating miRNA-associated signaling networks may offer a powerful platform for understanding mechanisms leading to impairments of cortical INs in neurodevelopmental and neuropsychiatric disorders, such as schizophrenia and autism (Tu et al, 2018;Lim et al, 2021).…”