Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence

Abstract

Background: Although the study of gene regulation via the action of specific microRNAs (miRNAs) has experienced a boom in recent years, the analysis of genome-wide interaction networks among miRNAs and respective targeted mRNAs has lagged behind. MicroRNAs simultaneously target many transcripts and fine-tune the expression of genes through cooperative/combinatorial targeting. Therefore, they have a large regulatory potential that could widely impact development and progression of diseases, as well as contribute unpredicted collateral effects due to their natural, pathophysiological, or treatment-induced modulation. We support the viewpoint that whole mirnome-transcriptome interaction analysis is required to better understand the mechanisms and potential consequences of miRNA regulation and/or deregulation in relevant biological models. In this study, we tested the hypotheses that ethanol consumption induces changes in miRNA-mRNA interaction networks in the mouse frontal cortex and that some of the changes observed in the mouse are equivalent to changes in similar brain regions from human alcoholics. Results: miRNA-mRNA interaction networks responding to ethanol insult were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA). Important pathways (coexpressed modular networks detected by WGCNA) and hub genes central to the neuronal response to ethanol are highlighted, as well as key miRNAs that regulate these processes and therefore represent potential therapeutic targets for treating alcohol addiction. Importantly, we discovered a conserved signature of changing miRNAs between ethanol-treated mice and human alcoholics, which provides a valuable tool for future biomarker/diagnostic studies in humans. We report positively correlated miRNA-mRNA expression networks that suggest an adaptive, targeted miRNA response due to binge ethanol drinking.

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

“…Consistent with previous observations, miRNA-339-5p was found to be upregulated in mouse alcohol-induced brain damage [32]. We found that ethanol itself could induce miR-339-5p expression; meanwhile, Tβ4 treatment could induce a significant increase in miR-339-5p expression in BV2 cells exposed to ethanol.…”

Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption

“…We used a combination of unbiased methods to reveal key microRNAs and their targets. Chronic alcohol consumption caused robust changes in synaptic microRNA expression levels consistent with those seen in human alcoholics (Lewohl et al, 2011) and in other animal models of dependence Alcohol-responsive synaptic microRNAs and mRNAs D Most et al Nunez et al, 2013;Tapocik et al, 2013). We further identified microRNAs with overlapping patterns of expression that correlated with alcohol consumption.…”

“…Little is known about the microRNAs involved in the regulation of synaptic mRNA translation during alcohol dependence. Studies investigating the effects of chronic alcohol consumption in standard tissue (total homogenate, TH) preparations found a persistent change in the expression of microRNAs and their target mRNAs in humans, mice, and rats (Lewohl et al, 2011;Gorini et al, 2013;Nunez et al, 2013;Tapocik et al, 2013). However, the standard TH preparation likely underestimates the number and magnitude of alcoholresponsive transcripts localized in the synapse (Lewohl et al, 2011;Most et al, 2014).…”

“…The extensive neuroadaptations associated with alcohol dependence are likely caused by persistent changes in the expression of hundreds of mRNAs (Mayfield et al, 2002;Ponomarev et al, 2012;Nunez et al, 2013). Many of the alcohol-responsive adaptations are related to synaptic structure and function and may be caused by coordinated changes in local mRNA translation Mayfield and Nunez, 2012).…”

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

“…Studies in this regard support this notion. For instance, a recent study in rats examining the effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum showed that widespread and tissue-specific changes in genome-wide methylation could mediate the activity of olanzapine while treating schizophrenia [93] . These examples raise the possibility that the mechanisms of action of certain approved drugs may involve previously uncharacterized epigenetic processes.…”