To test this hypothesis, we developed an integrated parameter synergy score which can be used to assess the nature and scale of miRNA synergy in human genome. We proposed that these two mechanisms can jointly contribute to synergistic miRNA actions. However, whether the synergistic actions could happen between miRNAs that target different genes was unknown. The miRNA-miRNA interaction network implies the existence of extensive synergies in the miRNA world, in which slight expression disturbance of miRNAs could collaboratively generate profound biological effects. suggested that miRNAs can impose synergistic gene regulation and demonstrate functional connections owing to targeting of common genes, collaboratively participating in the same processes. ĭespite that our knowledge about individual nodes of the miRNA network are rapidly accumulating, little is known about functional association and interactions between them. By means of network-based information integration of the currently available mass data of miRNA-target interactions and functional protein association, we revealed that miR-21 might play a core role in biological functions of major human tissues due to its preferential binding to ubiquitously expressed mRNAs. Thousands of miRNAs constitute into an additional functional layer in our biological system and contribute to its complexity, which has been recognized only until recently. For example, there has been 276 literature records of human target genes of miR-21, one of the most concerned miRNAs by far, , in the miRNA-target interaction database miRSel that updates daily. As the selective gene targeting of miRNAs is widely explored, the veil of mystery is being revealed about the mechanisms underlying their pervasive roles in human biology and disease. Up to now, there have been more than 2000 known mature human miRNA transcript records that can be retrieved from the 19.0 release of miRBase. MicroRNAs (miRNAs) can be classified as one super-family of small single-stranded non-coding RNA molecules that play roles in posttranscriptional gene regulation for fine-tuning protein abundance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by the Funds for Creative Research Groups (81121003), the National Natural Science Foundation of China (81072639) and Major Program of National Natural Science Foundation of China (81230081). Received: DecemAccepted: ApPublished: May 14, 2013Ĭopyright: © 2013 Zhu et al. Dalby, University of Westminster, United Kingdom (2013) Dissection of Protein Interactomics Highlights MicroRNA Synergy. Our results may be important for understanding synergistic gene regulation by miRNAs and may have significant implications for miRNA combination therapy of cardiovascular disease.Ĭitation: Zhu W, Zhao Y, Xu Y, Sun Y, Wang Z, Yuan W, et al. The novel approach established in this study enables easy and effective identification of condition-restricted potent miRNA synergy simply by concentrating the available protein interactomics and miRNA-target interaction data into a single parameter synergy score. The synergistic effect of miR-21 and miR-1 were functionally validated for their significant influences on myocardial apoptosis, cardiac hypertrophy and fibrosis. This result highlighted its essential role in coordinating or strengthening physiological and pathological functions of other miRNAs. Compared to other miRNAs, miR-21 was a highly exceptional case due to frequent appearance in the top synergistic miRNA pairs. However, targeting more key genes made two miRNAs more likely to act synergistically. Only a very small portion of the random miRNA-miRNA combinations generated potent synergy, implying poor expectancy of widespread synergy. Receiver operating characteristic (ROC) analysis indicated that synergy score accurately identified the gene ontology-defined miRNA synergy (AUC = 0.9415, p<0.001). Here we established an integrated parameter synergy score to determine miRNA synergy, by combining the two mechanisms for miRNA-miRNA interactions, miRNA-mediated gene co-regulation and functional association between target gene products, into one single parameter. Despite a large amount of microRNAs (miRNAs) have been validated to play crucial roles in human biology and disease, there is little systematic insight into the nature and scale of the potential synergistic interactions executed by miRNAs themselves.
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