Nunez Yury O, Truitt Jay M, Gorini Giorgio, Ponomareva Olga N, Blednov Yuri A, Harris R Adron, Mayfield R Dayne
The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA.
BMC Genomics. 2013 Oct 22;14:725. doi: 10.1186/1471-2164-14-725.
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.
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.
This study provides new evidence for the role of miRNA regulation in brain homeostasis and sheds new light on current understanding of the development of alcohol dependence. To our knowledge this is the first report that activated expression of miRNAs correlates with activated expression of mRNAs rather than with mRNA downregulation in an in vivo model. We speculate that early activation of miRNAs designed to limit the effects of alcohol-induced genes may be an essential adaptive response during disease progression.
尽管近年来通过特定微小RNA（miRNA）的作用对基因调控的研究蓬勃发展，但miRNA与各自靶向mRNA之间全基因组相互作用网络的分析却滞后了。微小RNA同时靶向许多转录本，并通过协同/组合靶向微调基因表达。因此，它们具有巨大的调控潜力，可能广泛影响疾病的发展和进程，并因其天然、病理生理或治疗诱导的调节作用而产生意想不到的附带效应。我们支持这样一种观点，即需要进行全基因组转录组相互作用分析，以更好地理解miRNA调控和/或失调在相关生物学模型中的机制和潜在后果。在本研究中，我们检验了以下假设：乙醇摄入会诱导小鼠额叶皮质中miRNA-mRNA相互作用网络发生变化，并且在小鼠中观察到的一些变化与人类酗酒者相似脑区的变化相当。
通过差异表达分析和加权基因共表达网络分析（WGCNA）确定了对乙醇损伤有反应的miRNA-mRNA相互作用网络。突出了重要的途径（通过WGCNA检测到的共表达模块网络）以及对乙醇神经元反应至关重要的枢纽基因，以及调节这些过程的关键miRNA，因此它们代表了治疗酒精成瘾的潜在治疗靶点。重要的是，我们发现了乙醇处理小鼠和人类酗酒者之间miRNA变化的保守特征，这为未来人类生物标志物/诊断研究提供了有价值的工具。我们报告了正相关的miRNA-mRNA表达网络，表明由于暴饮乙醇导致了适应性的、靶向性的miRNA反应。
本研究为miRNA调控在脑内稳态中的作用提供了新证据，并为当前对酒精依赖发展的理解提供了新的线索。据我们所知，这是第一份报告表明在体内模型中miRNA的激活表达与mRNA的激活表达相关，而不是与mRNA下调相关。我们推测，旨在限制酒精诱导基因作用的miRNA的早期激活可能是疾病进展过程中的一种重要适应性反应。
