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RNA Biol. 2013 Jul;10(7):1125-35. doi: 10.4161/rna.24955. Epub 2013 May 9.

The human transcriptome is enriched for miRNA-binding sites located in cooperativity-permitting distance.

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Institute of Computational Biology; Helmholtz Zentrum München; Neuherberg, Germany; Institute of Pharmacology 
and Toxicology; Technische Universität München; Munich, Germany.


MiRNAs are short, non-coding RNAs that regulate gene expression post-transcriptionally through specific binding to mRNA. Deregulation of miRNAs is associated with various diseases and interference with miRNA function has proven therapeutic potential. Most mRNAs are thought to be regulated by multiple miRNAs and there is some evidence that such joint activity is enhanced if a short distance between sites allows for cooperative binding. Until now, however, the concept of cooperativity among miRNAs has not been addressed in a transcriptome-wide approach. Here, we computationally screened human mRNAs for distances between miRNA binding sites that are expected to promote cooperativity. We find that sites with a maximal spacing of 26 nucleotides are enriched for naturally occurring miRNAs compared with control sequences. Furthermore, miRNAs with similar characteristics as indicated by either co-expression within a specific tissue or co-regulation in a disease context are predicted to target a higher number of mRNAs cooperatively than unrelated miRNAs. These bioinformatic data were compared with genome-wide sets of biochemically validated miRNA targets derived by Argonaute crosslinking and immunoprecipitation (HITS-CLIP and PAR-CLIP). To ease further research into combined and cooperative miRNA function, we developed miRco, a database connecting miRNAs and respective targets involved in distance-defined cooperative regulation ( In conclusion, our findings suggest that cooperativity of miRNA-target interaction is a widespread phenomenon that may play an important role in miRNA-mediated gene regulation.


cooperativity; microRNA; target prediction; target regulation

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