Institute of Human Genetics, Saarland University, 66421, Homburg, Germany.
Department of Experimental and Clinical Pharmacology & Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany.
Cell Mol Biol Lett. 2023 Jan 24;28(1):8. doi: 10.1186/s11658-023-00421-4.
Among the concepts in biology that are widely taken granted is a potentiated cooperative effect of multiple miRNAs on the same target. This strong hypothesis contrasts insufficient experimental evidence. The quantity as well as the quality of required side constraints of cooperative binding remain largely hidden. For miR-21-5p and miR-155-5p, two commonly investigated regulators across diseases, we selected 15 joint target genes. These were chosen to represent various neighboring 3'UTR binding site constellations, partially exceeding the distance rules that have been established for over a decade. We identified different cooperative scenarios with the binding of one miRNA enhancing the binding effects of the other miRNA and vice versa. Using both, reporter assays and whole proteome analyses, we observed these cooperative miRNA effects for genes that bear 3'UTR binding sites at distances greater than the previously defined limits. Astonishingly, the experiments provide even stronger evidence for cooperative miRNA effects than originally postulated. In the light of these findings the definition of targetomes specified for single miRNAs need to be refined by a concept that acknowledges the cooperative effects of miRNAs.
在生物学中，有一个被广泛接受的概念，即多个 miRNA 对同一个靶标具有增强的协同作用。这个强有力的假设与不足的实验证据形成鲜明对比。协同结合所需的边约束的数量和质量在很大程度上仍然隐藏着。对于 miR-21-5p 和 miR-155-5p，这两种在疾病中普遍被研究的调节剂，我们选择了 15 个共同的靶基因。这些基因被选择来代表各种相邻的 3'UTR 结合位点组合，部分超出了十多年来建立的距离规则。我们确定了不同的协同情景，其中一种 miRNA 的结合增强了另一种 miRNA 的结合效应，反之亦然。使用报告基因检测和全蛋白质组分析，我们观察到在距离大于先前定义的限制的 3'UTR 结合位点的基因上存在这些协同 miRNA 效应。令人惊讶的是，实验提供的证据甚至比最初假设的更有力地支持了 miRNA 的协同效应。鉴于这些发现，需要通过承认 miRNA 协同作用的概念来完善针对单个 miRNA 指定的靶基因组的定义。
