Outside the limit: questioning the distance restrictions for cooperative miRNA binding sites

Cellular & Molecular Biology Letters

Research Letter

Andreas Keller¹  Claudia Fecher-Trost²  Veit Flockerzi²  Markus R. Meyer³  Caroline Diener⁴  Martin Hart⁴  Eckart Meese⁴  Jessica Knittel⁴  Jens Mayer⁴  Stefanie Rheinheimer⁴ 

[1] Chair for Clinical Bioinformatics, Saarland Informatics Campus, Saarland University, 66123, Saarbrücken, Germany;Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Centre for Infection Research (HZI), 66123, Saarbrücken, 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;Department of Experimental and Clinical Toxicology & Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany;Institute of Human Genetics, Saarland University, 66421, Homburg, Germany;

关键词: microRNA;    Cooperativity;    Binding sites;    Distances;    In silico prediction;    RISC;    Functional interactions;    Networks;    Proteomics;    Target identification;   

DOI  :  10.1186/s11658-023-00421-4

 received in 2022-10-07, accepted in 2023-01-16,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023

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