A Novel Method to Detect Functional microRNA Regulatory Modules by Bicliques Merging

Cheng Liang, Yue Li, Jiawei Luo

MicroRNAs (miRNAs) are post-transcriptional regulators that repress the expression of their targets. They are known to work cooperatively with genes and play important roles in numerous cellular processes. Identification of miRNA regulatory modules (MRMs) would aid deciphering the combinatorial effects derived from the many-to-many regulatory relationships in complex cellular systems. Here, we develop an effective method called BiCliques Merging (BCM) to predict MRMs based on bicliques merging. By integrating the miRNA/mRNA expression profiles from The Cancer Genome Atlas (TCGA) with the computational target predictions, we construct a weighted miRNA regulatory network for module discovery. The maximal bicliques detected in the network are statistically evaluated and filtered accordingly. We then employed a greedy-based strategy to iteratively merge the remaining bicliques according to their overlaps together with edge weights and the gene-gene interactions. Comparing with existing methods on two cancer datasets from TCGA, we showed that the modules identified by our method are more densely connected and functionally enriched. Moreover, our predicted modules are more enriched for miRNA families and the miRNA-mRNA pairs within the modules are more negatively correlated. Finally, several potential prognostic modules are revealed by Kaplan-Meier survival analysis and breast cancer subtype analysis. BCM is implemented in Java and available for download in the supplementary materials, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/ TCBB.2015.2462370.