New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites
New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites
复制标题
DOI：
10.1101/gr.089367.108
复制
发表时间：
2009-07-01
期刊：
影响因子：
7
通讯作者：
Athey, Brian D.
中科院分区：
文献类型：
--
作者：
Lee, Inhan;Ajay, Subramanian S.;Athey, Brian D.
微小RNA（miRNAs）已知通过3'-非翻译区（3'-UTR）在转录后调控靶mRNA，在动物中其主要与miRNA的5'-端相互作用。在此我们在人类5'-非翻译区（5'-UTRs）中鉴定出许多针对miRNAs 3'-端的内源性基序。特别是保守的miRNAs的3'-端在人类富集的、保守性较差的5'-UTR miRNA基序中有显著的相互作用位点，而人类特异性miRNAs仅在保守的5'-UTR基序中有显著的相互作用位点，这意味着miRNA和5'-UTR都在相互作用中积极进化。此外，许多在5'-UTRs中有3'-端相互作用位点的miRNAs同时在3'-UTRs中包含5'-端相互作用位点。基于这些发现，我们利用模型系统展示了单个miRNA与mRNA的两个末端区域之间的组合相互作用。我们进一步表明，由于miRNA过表达或缺失而表现出大规模蛋白质变化的基因包含所预测的两个非翻译区（UTR）相互作用位点。我们提供了这种新的miRNA靶标类别（miBridge）的预测靶标，作为一种筛选潜在靶标的有效方法，特别是对于非保守的miRNAs，因为与仅使用3'-UTR相比，靶标搜索空间缩小了一个数量级。通过展示仅在灵长类中鉴定的hsa - miR - 605对SEC24D的调控，证实了其有效性，这为非保守miRNAs的研究打开了大门。最后，参与这种新靶向类别的miRNAs（以及相关蛋白质）可能阻止40S核糖体通过5'-UTR进行扫描，并使其无法到达起始密码子，从而阻止60S结合。
MicroRNAs (miRNAs) are known to post-transcriptionally regulate target mRNAs through the 3'-UTR, which interacts mainly with the 5'-end of miRNA in animals. Here we identify many endogenous motifs within human 5'-UTRs specific to the 3'-ends of miRNAs. The 3'-end of conserved miRNAs in particular has significant interaction sites in the human-enriched, less conserved 5'-UTR miRNA motifs, while human-specific miRNAs have significant interaction sites only in the conserved 5'-UTR motifs, implying both miRNA and 5'-UTR are actively evolving in response to each other. Additionally, many miRNAs with their 3'-end interaction sites in the 5'-UTRs turn out to simultaneously contain 5'-end interaction sites in the 3'-UTRs. Based on these findings we demonstrate combinatory interactions between a single miRNA and both end regions of an mRNA using model systems. We further show that genes exhibiting large-scale protein changes due to miRNA overexpression or deletion contain both UTR interaction sites predicted. We provide the predicted targets of this new miRNA target class, miBridge, as an efficient way to screen potential targets, especially for nonconserved miRNAs, since the target search space is reduced by an order of magnitude compared with the 3'-UTR alone. Efficacy is confirmed by showing SEC24D regulation with hsa-miR-605, a miRNA identified only in primate, opening the door to the study of nonconserved miRNAs. Finally, miRNAs (and associated proteins) involved in this new targeting class may prevent 40S ribosome scanning through the 5'-UTR and keep it from reaching the start-codon, preventing 60S association.