Cotargeting among microRNAs in the brain
Cotargeting among microRNAs in the brain
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DOI：
10.1101/gr.249201.119
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发表时间：
2019-11-01
期刊：
影响因子：
7
通讯作者：
Burge, Christopher B.
中科院分区：
文献类型：
--
作者：
Cherone, Jennifer M.;Jorgji, Vjola;Burge, Christopher B.
microRNAs（miRNAs）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。通过不同的miRNA共同靶向单个mRNA可能会实现更强和更复杂的抑制模式。通过比较不同miRNA的靶标组，我们鉴定了数百对miRNA，它们相对于严格对照共享比预期更多的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在神经元分化中的功能重叠。所有共同靶向对的聚类显示了一组9个主要的脑富集miRNA，它们共享许多靶点。在报告基因分析中，这些miRNA的子集共同抑制基因表达5至10倍，通常表现出协同抑制。总之，我们的研究结果揭示了一种意想不到的模式，其中miRNAs的组合协作强烈抑制cotargets，并表明cotargeting的重要发育作用。
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.