3′ Uridylation Confers miRNAs with Non-canonical Target Repertoires
3′ Uridylation Confers miRNAs with Non-canonical Target Repertoires
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DOI：
10.1016/j.molcel.2019.05.014
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发表时间：
2019-08-08
期刊：
影响因子：
16
通讯作者：
Gu, Shuo
中科院分区：
文献类型：
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作者：
Yang, Acong;Bofill-De Ros, Xavier;Gu, Shuo
许多微小RNA（miRNA）与丰富的miRNA同种型（isomiR）一起存在，其中大多数来自成熟后序列修饰，例如3'尿苷酸化。然而，这些序列修饰影响miRNA功能的方式仍然知之甚少。在这里，使用细胞系中的人miR-27 a作为模型，我们发现当上游腺苷能够与miR-27 a尾中转录后添加的尿苷碱基配对时，不能与miRNA种子序列广泛碱基配对的非功能性靶位点可以恢复功能。这种尾U介导的抑制（TUMR）在缺乏尿苷酸化酶TUT 4和TUT 7的细胞中被消除，表明尿苷酸化通过调节靶识别来改变miRNA功能。我们在人类细胞中鉴定了一组由尿苷化miR-27 a特异性调控的非经典靶点。我们提供的证据表明，TUMR扩展了其他内源性miRNA的靶点。我们的研究揭示了尿苷化的isomiRs在调节非经典miRNA靶点中的功能。
Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3' uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets.