miRCoop: Identifying Cooperating miRNAs via Kernel Based Interaction Tests

Although miRNAs can cause widespread changes on expression programs, single miRNAs typically induce mild repression on their targets. Cooperativity is reported as one strategy to overcome this constraint. Expanding the catalog of synergistic miRNAs is critical for understanding the regulation of various gene expression programs. In this study, we develop miRCoop to identify synergistic miRNA pairs which have weak or no repression on the target mRNA, but when bound together induce strong repression of their target9s expression. To discover triplets of RNAs whose expression levels follow these statistical interaction patterns, miRCoop uses kernel-based interaction tests together with miRNA and mRNA target information. We apply our approach to kidney tumor and identify 66 putative triplets. For 64 of these triplets, there is at least one common transcription factor that potentially regulates all participating RNAs of the triplet supporting a functional association among them. Furthermore, we find triplets are enriched for biological processes, which are relevant to kidney cancer. Some of the synergistic miRNAs are very closely encoded in the genome hinting a functional association among them. We believe miRCoop can aid our understanding of the complex regulatory interactions in different health and disease states of the cell.