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. 2011 Feb;39(3):825-36.
doi: 10.1093/nar/gkq832. Epub 2010 Oct 6.

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features

Juan Xu  1 , Chuan-Xing Li, Yong-Sheng Li, Jun-Ying Lv, Ye Ma, Ting-Ting Shao, Liang-De Xu, Ying-Ying Wang, Lei Du, Yun-Peng Zhang, Wei Jiang, Chun-Quan Li, Yun Xiao, Xia Li
Affiliations

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features

Juan Xu et al. Nucleic Acids Res. 2011 Feb.

Abstract

Synergistic regulations among multiple microRNAs (miRNAs) are important to understand the mechanisms of complex post-transcriptional regulations in humans. Complex diseases are affected by several miRNAs rather than a single miRNA. So, it is a challenge to identify miRNA synergism and thereby further determine miRNA functions at a system-wide level and investigate disease miRNA features in the miRNA-miRNA synergistic network from a new view. Here, we constructed a miRNA-miRNA functional synergistic network (MFSN) via co-regulating functional modules that have three features: common targets of corresponding miRNA pairs, enriched in the same gene ontology category and close proximity in the protein interaction network. Predicted miRNA synergism is validated by significantly high co-expression of functional modules and significantly negative regulation to functional modules. We found that the MFSN exhibits a scale free, small world and modular architecture. Furthermore, the topological features of disease miRNAs in the MFSN are distinct from non-disease miRNAs. They have more synergism, indicating their higher complexity of functions and are the global central cores of the MFSN. In addition, miRNAs associated with the same disease are close to each other. The structure of the MFSN and the features of disease miRNAs are validated to be robust using different miRNA target data sets.

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Figures

Figure 1.
Figure 1.
The workflow to construct the MFSN and two examples of synergism among miRNA with their co-regulating functional modules. (A) Workflow to construct the miRNA–miRNA functional synergistic network (MFSN) via co-regulating functional modules. The process involves two main steps. First, we identified an miRNA pair that synergistically regulates at least one functional module. Second, we repeated the first step for any miRNA pairs, and assembled all the significant miRNA pairs to construct the MFSN. (B) Two examples of miRNA pairs that synergistically regulate functional modules; these co-regulations are associated with diseases. Non-direct dashed line represents the miRNA synergistic action; direct line represents the miRNA regulation to the functional module.
Figure 2.
Figure 2.
The layout of the MFSN and its structural features. (A) The MFSN generated by the procedure is described in the ‘Materials and Methods’ section. This network consists of 473 miRNAs and 2937 co-regulatory links. A node represents a miRNA, and an edge represents a synergistic action. An diamond marks the location of miRNAs associated with epithelial ovarian cancer, and a triangle marks the location of those associated with type 2 diabetes in Figure 3B. Pentacles mark the location of communities in Figure 4 with three k-values. (B) Degree distribution of the MFSN. (C) Number of cliques at different k-values and cumulative ratios of miRNAs in cliques with k-values are not bigger than k. The left y-axis represents number of cliques under different k-values, corresponding to the solid line. The right y-axis represents cumulative ratios of miRNAs in cliques, corresponding to the dashed line.
Figure 3.
Figure 3.
Distinct topological features of disease miRNAs and two examples of diseases. (A) The mean characteristic path length among miRNAs for the same disease is shorter than both kinds of randomization tests. The arrow represents the mean characteristic path length in the real network, the line of light color is fitted using random selecting miRNAs from disease miRNAs and the line of dark color presents all miRNAs in the MFSN. (B) Two examples of characteristic path lengths (Chpath) of diseases. In the upper panel, nodes of dark color represent epithelial ovarian cancer-associated miRNAs; the inset panel shows location of the diamond in Figure 2A. The lower panel shows miRNAs associated with type 2 diabetes, and nodes of dark color represent associated miRNAs; the inset panel is located at the triangle in Figure 2A. (C) The difference in degrees between disease miRNAs and non-disease miRNAs with two types of data. Boxes of light color represent the distribution of disease miRNA degrees, and the black boxes correspond to non-disease miRNAs. P-values are calculated using the Wilcoxon rank-sum test.
Figure 4.
Figure 4.
Communities with k-values of 9, 10 and 11 show the tendency of location of disease miRNAs that are located at the pentacles in Figure 2A. Nodes of dark color represent disease miRNAs; miRNAs on the background occur in at least two communities.
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References

    1. Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB, Bartel DP. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science. 2005;310:1817–1821. - PubMed
    1. Friedman JM, Jones PA. MicroRNAs: critical mediators of differentiation, development and disease. Swiss Med. Wkly. 2009;139:466–472. - PMC - PubMed
    1. Migliore C, Giordano S. MiRNAs as new master players. Cell Cycle. 2009;8:2185–2186. - PubMed
    1. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat. Genet. 2005;37:766–770. - PubMed
    1. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115:787–798. - PubMed

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