MicroRNAs (miRNAs) play roles in diverse developmental and disease processes. Distinct miRNAs have hundreds to thousands of conserved mRNA binding sites but typically direct only modest repression via single sites. Cotargeting of individual mRNAs by different miRNAs could potentially achieve stronger and more complex patterns of repression. By comparing target sets of different miRNAs, we identified hundreds of pairs of miRNAs that share more mRNA targets than expected (often by twofold or more) relative to stringent controls. Genetic perturbations revealed a functional overlap in neuronal differentiation for the cotargeting pair miR-138/miR-137. Clustering of all cotargeting pairs revealed a group of nine predominantly brain-enriched miRNAs that share many targets. In reporter assays, subsets of these miRNAs together repressed gene expression by five- to 10-fold, often showing cooperative repression. Together, our results uncover an unexpected pattern in which combinations of miRNAs collaborate to robustly repress cotargets, and suggest important developmental roles for cotargeting.

中文翻译：

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大脑中 microRNA 之间的共同靶向。

MicroRNA (miRNA) 在多种发育和疾病过程中发挥作用。不同的 miRNA 具有数百至数千个保守的 mRNA 结合位点，但通常仅通过单个位点进行适度的抑制。不同 miRNA 共同靶向单个 mRNA 可能会实现更强、更复杂的抑制模式。通过比较不同 miRNA 的靶标集，我们鉴定了数百对 miRNA，它们与严格对照相比，共享比预期更多的 mRNA 靶标（通常是两倍或更多）。遗传扰动揭示了共靶向对 miR-138/miR-137 神经元分化的功能重叠。所有共靶向对的聚类揭示了一组九个主要富含大脑的 miRNA，它们共享许多靶点。在报告基因检测中，这些 miRNA 的子集一起抑制基因表达 5 到 10 倍，通常表现出协同抑制。总之，我们的结果揭示了一种意想不到的模式，其中 miRNA 的组合协作有力地抑制共靶标，并表明共靶标的重要发育作用。