Differential Sensitivity of Target Genes to Translational Repression by miR-17~92.
Differential Sensitivity of Target Genes to Translational Repression by miR-17~92.
复制标题
靶基因对 miR-17 翻译抑制的敏感性差异与 92 相似
DOI：
10.1371/journal.pgen.1006623
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发表时间：
2017-02
期刊：
影响因子：
4.5
通讯作者：
Xiao C
中科院分区：
文献类型：
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作者：
Jin HY;Oda H;Chen P;Yang C;Zhou X;Kang SG;Valentine E;Kefauver JM;Liao L;Zhang Y;Gonzalez-Martin A;Shepherd J;Morgan GJ;Mondala TS;Head SR;Kim PH;Xiao N;Fu G;Liu WH;Han J;Williamson JR;Xiao C
微RNA（miRNAs）被认为通过调节数百个靶基因的表达来发挥其功能，并且每个靶基因的表达都在很小的程度上，但目前尚不清楚数百个靶基因中的微小变化如何转化为miRNA的特定功能。为了解决这一问题，我们对来自表达三种不同水平miR-17~92的突变小鼠的原代B细胞的转录组和翻译组进行了综合分析。我们发现靶基因对miRNA抑制表现出不同的敏感性，并且在生理条件下，只有一小部分靶基因实际上被给定浓度的miRNA抑制。相同miRNA基因的转基因表达和缺失在很大程度上调节不同的靶基因组。miR-17~92主要通过翻译抑制来调控靶基因的表达，而5 'UTR在调节靶基因对miRNA抑制的敏感性中起重要作用。这些发现为miRNAs通过少量关键靶基因发挥其特定功能的模型提供了分子见解。MicroRNA（miRNAs）是由我们的基因组编码的小RNA。每个miRNA结合数百个靶mRNA并执行特定功能。人们认为，miRNA通过降低所有这些靶基因的表达来发挥其功能，并且每个基因的表达都在很小程度上减少。然而，这些靶基因通常具有非常不同的功能。目前还不清楚数百个具有不同功能的靶基因中的微小变化如何转化为miRNA的特定功能。本研究利用最新的技术进展，在转基因过表达或缺失miR-17~92的突变小鼠中，对第一个致癌miRNA miR-17~92调控的868个靶基因的mRNA和蛋白水平进行了全面的检测。我们发现miR-17~92主要在蛋白水平调控靶基因的表达，对mRNA的影响很小。令人惊讶的是，只有一小部分靶基因对miR-17~92表达变化有反应。进一步的研究表明，靶基因对miR-17~92的敏感性是由靶mRNA的非编码区决定的。我们的研究结果表明，并非每个靶基因都是平等的，并表明miRNA的功能是由少数关键靶基因介导的。
MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. MicroRNAs (miRNAs) are small RNAs encoded by our genome. Each miRNA binds hundreds of target mRNAs and performs specific functions. It is thought that miRNAs exert their function by reducing the expression of all these target genes and each to a small degree. However, these target genes often have very diverse functions. It has been unclear how small changes in hundreds of target genes with diverse functions are translated into the specific function of a miRNA. Here we take advantage of recent technical advances to globally examine the mRNA and protein levels of 868 target genes regulated by miR-17~92, the first oncogenic miRNA, in mutant mice with transgenic overexpression or deletion of this miRNA gene. We show that miR-17~92 regulates target gene expression mainly at the protein level, with little effect on mRNA. Surprisingly, only a small fraction of target genes respond to miR-17~92 expression changes. Further studies show that the sensitivity of target genes to miR-17~92 is determined by a non-coding region of target mRNA. Our findings demonstrate that not every target gene is equal, and suggest that the function of a miRNA is mediated by a small number of key target genes.