Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT
Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT
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DOI：
10.1016/j.cels.2018.05.019
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发表时间：
2018-07-25
期刊：
影响因子：
9.3
通讯作者：
Davis, Melissa J.
中科院分区：
文献类型：
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作者：
Cursons, Joseph;Pillman, Katherine A.;Davis, Melissa J.
MicroRNAs （miRNAs）是基因表达的重要转录后调节因子，其部分功能是促进靶mrna的降解。它们在控制上皮-间充质转化（EMT）中发挥着既定的作用，这是一种正常和病理过程基础上的可逆表型程序。许多研究表明，单个mirna的过表达水平大大超过生理丰度。这可以影响靶向性相对较差的转录本，并可能部分解释为什么超过130种不同的mirna直接参与EMT调控。分析EMT的人乳腺细胞模型，我们发现一组mirna，包括miR-200和miR-182/183家族成员，在转录后调控中合作，加强和缓冲转录输出。为此，我们证明了组合治疗改变了细胞表型，miRNA浓度更接近内源性水平，脱靶效应更小。这表明mirna的协同靶向对其生理功能很重要，未来的mirna分类工作应考虑这种组合效应。
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation of target mRNAs. They have an established role in controlling epithelial- mesenchymal transition (EMT), a reversible phenotypic program underlying normal and pathological processes. Many studies demonstrate the role of individual miRNAs using overexpression at levels greatly exceeding physiological abundance. This can influence transcripts with relatively poor targeting and may in part explain why over 130 different miRNAs are directly implicated as EMT regulators. Analyzing a human mammary cell model of EMT we found evidence that a set of miRNAs, including the miR-200 and miR-182/183 family members, cooperate in post-transcriptional regulation, both reinforcing and buffering transcriptional output. Investigating this, we demonstrate that combinatorial treatment altered cellular phenotype with miRNA concentrations much closer to endogenous levels and with less off-target effects. This suggests that co-operative targeting by miRNAs is important for their physiological function and future work classifying miRNAs should consider such combinatorial effects.