MiRNA-miRNA Synergistic Network: Construction,Topological Features Of Disease MiRNAs And Similarity In Sequence And Structure

MicroRNAs are endogenous non-coding (~22nucleotide) RNAs that regulate theexpression of target mRNAs at the post-transcriptional level. They play critical rolesin various biological and metabolic processes such as cell proliferation, signaltransduction, development and apoptosis. Thus, it is intuitive that the abnormality ofmiRNA function can deeply impact multiple features of cell biology, ultimatelyresulting in complex pathological events including cancers. Some researchers claimedthat the human genome might encode more than1,100miRNAs and it was recentlydemonstrated that they potentially regulate the majority of all human genes, which cantherefore be used to improve our understanding of the mode of action of miRNAs andtheir functions. The limited miRNAs are thought to be able to control the larger set ofgenes through synergism, in which multiple miRNAs work synergistically to controlindividual genes. Therefore, synergistic regulations among multiple microRNAs areimportant to understand the mechanisms of complex post-transcriptional regulationsin humans. Complex diseases are affected by several miRNAs rather than a singlemiRNA. So, it is a challenge to identify miRNA synergism, thereby further determinemiRNA functions at a system-wide level and investigate disease miRNA features inthe miRNA-miRNA synergistic network from a new view. It is also nessesary toanalyze the sequence or structrue association between miRNAs with synergism.Here we constructed a miRNA-miRNA functional synergistic network (MFSN) viaco-regulating functional modules which have three features: common targets ofcorresponding miRNA pairs, enriched in the same Gene Ontology category and closeproximity in the protein interaction network. If a miRNA pair co-regulates at least onefunctional module, they are considered to be synergism. Predicted miRNA synergismis validated by significantly high co-expression of functional modules andsignificantly negative regulation to functional modules. The MFSN exhibits scale-free,small-world and modular architecture, so it has many advantages of structure as general biological networks such as protein interaction networks or friendshipnetworks in sociology. The structure of the MFSN is validated to be robust usingdifferent miRNA target datasets.Furthermore, the topological features of disease miRNAs in the MFSN aresignificantly distinct from non-disease miRNAs. They have more synergism whichindicates their higher functional complexity. Most disease miRNAs are located in theoverlap region of most tightly connected communities, as the global central cores ofthe MFSN. In addition, miRNAs for the same disease are close with each other in theMFSN to regulate targets with the same or similar functions. The topological featuresof disease miRNAs are validated to be robust using different miRNA target datasets.Finaly, we systemically analyzed the association between miRNAs with synergismat the view of sequence, tructure and transcriptional regulation. We found thatsynergistic miRNAs have significantly higher similarity of sequence or tructure thannon-synergistic miRNA pairs. Especially synergistic miRNAs pairs with the highestsimilarity are mostly from the same miRNA families, with decresing the thresholdvalue of similarity, the proportion of synergism between miRNAs from differentfamilies’ increases. The similarity of miRNA synergistic modules is significantlyhigher than the general level of the MFSN. In addition, the sequence similarity ofsynergistic miRNAs is significantly positive with their functional concordance, so thesequence similarity might reveal the functional association between miRNAs, to acertain extent. Althogh the structure similarity is not significant associated with thefunctional association, we found several miRNA synergism could be explained by it.We also found that synergistic miRNAs significantly share transcriptional factors(TFs), and their regulational concordance is higher than non-synergistic miRNA pairs.Most miRNA pairs with highest regulational concordance are from the same miRNAfamilies. At last, miRNAs sharing TFs tend to be the centre of the MFSN.Overall, miRNA-miRNA functional synergistic network not only increases our understanding of their mechanism in post-transcriptional regulation, but also providesa new insight into the global topological properties of disease miRNAs.