Langfelder Peter, Gao Fuying, Wang Nan, Howland David, Kwak Seung, Vogt Thomas F, Aaronson Jeffrey S, Rosinski Jim, Coppola Giovanni, Horvath Steve, Yang X William
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, United States of America.
PLoS One. 2018 Jan 11;13(1):e0190550. doi: 10.1371/journal.pone.0190550. eCollection 2018.
In Huntington's disease (HD) patients and in model organisms, messenger RNA transcriptome has been extensively studied; in contrast, comparatively little is known about expression and potential role of microRNAs. Using RNA-sequencing, we have quantified microRNA expression in four brain regions and liver, at three different ages, from an allelic series of HD model mice with increasing CAG length in the endogenous Huntingtin gene. Our analyses reveal CAG length-dependent microRNA expression changes in brain, with 159 microRNAs selectively altered in striatum, 102 in cerebellum, 51 in hippocampus, and 45 in cortex. In contrast, a progressive CAG length-dependent microRNA dysregulation was not observed in liver. We further identify microRNAs whose transcriptomic response to CAG length expansion differs significantly among the brain regions and validate our findings in data from a second, independent cohort of mice. Using existing mRNA expression data from the same animals, we assess the possible relationships between microRNA and mRNA expression and highlight candidate microRNAs that are negatively correlated with, and whose predicted targets are enriched in, CAG-length dependent mRNA modules. Several of our top microRNAs (Mir212/Mir132, Mir218, Mir128 and others) have been previously associated with aspects of neuronal development and survival. This study provides an extensive resource for CAG length-dependent changes in microRNA expression in disease-vulnerable and -resistant brain regions in HD mice, and provides new insights for further investigation of microRNAs in HD pathogenesis and therapeutics.
在亨廷顿舞蹈病（HD）患者和模式生物中，信使核糖核酸转录组已得到广泛研究；相比之下，人们对微小核糖核酸（miRNA）的表达及其潜在作用了解较少。我们利用RNA测序技术，对内源亨廷顿基因中CAG长度不断增加的HD模型小鼠等位基因系列在三个不同年龄阶段的四个脑区和肝脏中的miRNA表达进行了定量分析。我们的分析揭示了大脑中miRNA表达随CAG长度的变化，纹状体中有159种miRNA选择性改变，小脑中有102种，海马体中有51种，皮质中有45种。相比之下，在肝脏中未观察到随CAG长度增加而逐渐出现的miRNA失调。我们进一步鉴定了在不同脑区中对CAG长度扩展的转录组反应存在显著差异的miRNA，并在来自另一独立小鼠队列的数据中验证了我们的发现。利用来自同一批动物的现有mRNA表达数据，我们评估了miRNA与mRNA表达之间的可能关系，并突出显示了与CAG长度依赖性mRNA模块呈负相关且其预测靶标在其中富集的候选miRNA。我们的几个顶级miRNA（Mir212/Mir132、Mir218、Mir128等）此前已与神经元发育和存活的某些方面相关联。本研究为HD小鼠疾病易感性和抗性脑区中miRNA表达随CAG长度的变化提供了丰富资源，并为进一步研究miRNA在HD发病机制和治疗中的作用提供了新见解。
