Nunez Yury O, Mayfield R Dayne
Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin Austin, TX, USA.
Front Genet. 2012 Apr 3;3:43. doi: 10.3389/fgene.2012.00043. eCollection 2012.
Advances in the fields of genomics and genetics in the last decade have identified a large number of genes that can potentially influence alcohol-drinking behavior in humans as well as animal models. Consequently, the task of identifying efficient molecular targets that could be used to develop effective therapeutics against the disease has become increasingly daunting. One of the reasons for this is the fact that each of the many alcohol-responsive genes only contributes a small effect to the overall mechanism and disease phenotype, as is characteristic of complex traits. Current research trends are hence shifting toward the analysis of gene networks rather than emphasizing individual genes. The discovery of microRNAs and their mechanisms of action on regulation of transcript level and protein translation have made evident the utility of these small non-coding RNA molecules that act as central coordinators of multiple cross-communicating cellular pathways. Cells exploit the fact that a single microRNA can target hundreds of mRNA transcripts and that a single mRNA transcript can be simultaneously targeted by distinct microRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions. By the same token, we can use these properties of microRNAs to develop novel, targeted strategies to combat complex disorders. In this review, we will focus on recent discoveries of microRNA signatures in brain of human alcoholics supporting the hypothesis that changes in gene expression and regulation by microRNAs are responsible for long-term neuroadaptations occurring during development of alcoholism. We also discuss insights into the potential modulation of epigenetic regulators by a subset of microRNAs. Taken together, microRNA activity may be controlling many of the cellular mechanisms already known to be involved in the development of alcoholism, and suggests potential targets for the development of novel therapeutic interventions.
在过去十年中，基因组学和遗传学领域的进展已经鉴定出大量可能影响人类以及动物模型饮酒行为的基因。因此，确定可用于开发针对该疾病有效疗法的高效分子靶点的任务变得越来越艰巨。原因之一是，许多酒精反应基因中的每一个对整体机制和疾病表型的影响都很小，这是复杂性状的特征。因此，当前的研究趋势正转向基因网络分析，而不是强调单个基因。微小RNA的发现及其对转录水平和蛋白质翻译调控的作用机制，已经证明了这些小的非编码RNA分子作为多个相互交流的细胞途径的中央协调者的效用。细胞利用单个微小RNA可以靶向数百个mRNA转录本，以及单个mRNA转录本可以同时被不同的微小RNA靶向这一事实，来确保对大量细胞功能进行微调控制和/或冗余控制。同样，我们可以利用微小RNA的这些特性来开发新的、有针对性的策略来对抗复杂疾病。在这篇综述中，我们将重点关注人类酗酒者大脑中微小RNA特征的最新发现，这些发现支持了微小RNA引起的基因表达和调控变化是酗酒发展过程中发生的长期神经适应的原因这一假设。我们还讨论了一部分微小RNA对表观遗传调节因子潜在调节作用的见解。综上所述，微小RNA活性可能控制着许多已知与酗酒发展有关的细胞机制，并为开发新的治疗干预措施提供了潜在靶点。
