Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. They play an important role in several biological processes such as cell development and differentiation. Similar to transcription factors (TFs), miRNAs regulate gene expression in a combinatorial fashion, i.e., an individual miRNA can regulate multiple genes, and an individual gene can be regulated by multiple miRNAs. The functions of TFs in biological regulatory networks have been well explored. And, recently, a few studies have explored miRNA functions in the context of gene regulation networks. However, how TFs and miRNAs function together in the gene regulatory network has not yet been examined. In this paper, we propose a new computational method to discover the gene regulatory modules that consist of miRNAs, TFs, and genes regulated by them. We analyzed the regulatory associations among the sets of predicted miRNAs and sets of TFs on the sets of genes regulated by them in the human genome. We found 182 gene regulatory modules of combinatorial regulation by miRNAs and TFs (miR-TF modules). By validating these modules with the Gene Ontology (GO) and the literature, it was found that our method allows us to detect functionally-correlated gene regulatory modules involved in specific biological processes. Moreover, our miR-TF modules provide a global view of coordinated regulation of target genes by miRNAs and TFs.