The role of site accessibility in microRNA target recognition
The role of site accessibility in microRNA target recognition
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DOI：
10.1038/ng2135
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发表时间：
2007-10-01
期刊：
影响因子：
30.8
通讯作者：
Segal, Eran
中科院分区：
文献类型：
--
作者：
Kertesz, Michael;Iovino, Nicola;Segal, Eran
microRNA是基因表达的关键调节因子（1-4），但其与mRNA靶点相互作用的确切机制仍知之甚少。在这里，我们系统地研究了靶位点可及性的作用，由mRNA内的碱基配对相互作用决定，在microRNA靶识别。我们的实验表明，减少靶可及性的突变大大减少了microRNA介导的翻译抑制，其效果与破坏序列互补性的突变相当。我们设计了一个无参数的microRNA-靶相互作用模型，该模型计算了从microRNA-靶双链体形成中获得的自由能与使靶不配对以使其接近microRNA的能量成本之间的差异。该模型解释了我们的实验中的变异性，比现有算法更准确地预测验证的目标，并表明基因组通过优先将目标定位在高度可访问的区域来适应网站的可访问性。因此，我们的研究表明，目标可及性是microRNA功能的关键因素。
MicroRNAs are key regulators of gene expression(1-4), but the precise mechanisms underlying their interaction with their mRNA targets are still poorly understood. Here, we systematically investigate the role of target-site accessibility, as determined by base-pairing interactions within the mRNA, in microRNA target recognition. We experimentally show that mutations diminishing target accessibility substantially reduce microRNA-mediated translational repression, with effects comparable to those of mutations that disrupt sequence complementarity. We devise a parameter-free model for microRNA-target interaction that computes the difference between the free energy gained from the formation of the microRNA-target duplex and the energetic cost of unpairing the target to make it accessible to the microRNA. This model explains the variability in our experiments, predicts validated targets more accurately than existing algorithms, and shows that genomes accommodate site accessibility by preferentially positioning targets in highly accessible regions. Our study thus demonstrates that target accessibility is a critical factor in microRNA function.