Up-Regulation of MicroRNAs in Brain of Human Alcoholics

Abstract

Background MicroRNAs (miRNAs) are small, non-coding oligonucleotides with an important role in post transcriptional regulation of gene expression at the level of translation and mRNA degradation. Recent studies have revealed that miRNAs play important roles in a variety of biological processes, such as cell proliferation, neuronal differentiation, developmental timing, synapse function and neurogenesis. A single miRNA can target hundreds of mRNA transcripts for either translation repression or degradation, but the function of many human miRNAs is not known. Methods MiRNA array analysis was performed on the prefrontal cortex of 27 individual human cases (14 alcoholics and 13 matched controls). Target genes for differentially expressed miRNAs were predicted using multiple target prediction algorithms and a consensus approach, and predicted targets were matched against differentially expressed mRNAs from the same samples. Over- and under-representation analysis was performed using hypergeometric probability and z-score tests. Results Approximately 35 miRNAs were significantly up-regulatedin the alcoholic group compared with controls. Target prediction showed a large degree of overlap with our published cDNA microarray data. Functional classification of the predicted target genes of the regulated miRNAs includes apoptosis, cell cycle, cell adhesion, nervous system development and cell-cell signaling. Conclusions This data suggests that the reduced expression of genes in human alcoholic cases may be due to the up-regulated miRNAs. Cellular processes fundamental to neuronal plasticity appear to represent major targets of the suggested miRNA regulation.

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.…”

“…This regimen of alcohol consumption causes extensive and coordinated changes in gene expression in the brain, suggesting a network regulator such as a microRNA may be involved (Lewohl et al, 2011). The question remains regarding how, or if, alcohol affects synaptic pathways through synaptic microRNA regulation.…”

“…For cell types and immune response enrichment, we used the following lists of genes: neurons, astrocytes and oligodendrocytes (Cahoy et al, 2008), microglia (cured from Oldham et al, 2008), and glutamate/GABA (Sugino et al, 2006). For cross species comparison, we used lists from alcohol vapor-treated rats (Tapocik et al, 2013) and human alcoholics (Lewohl et al, 2011) to identify conserved alcoholresponsive microRNAs. Drugs that potentially target the alcohol-responsive mRNAs and the 'mRNA targets of the alcohol-responsive microRNAs' were found using Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Qiagen, CA).…”

“…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).…”

“…Exposure to alcohol and other drugs of abuse modulates microRNA expression in the brain (Pietrzykowski et al, 2008;He et al, 2010;Eipper-Mains et al, 2011;Lewohl et al, 2011;Tapocik et al, 2013). MicroRNAs have important roles in learning and memory (Konopka et al, 2010), and are also altered in addiction-related behaviors, such as cocaineconditioned place preference (Chandrasekar and Dreyer, 2011), cocaine-seeking behavior , and selfadministration of alcohol (Tapocik et al, 2014).…”