Crosstalk between transcription factors and microRNAs in human protein interaction network

Background: Gene regulatory networks control the global gene expression and the dynamics of protein output in living cells. In multicellular organisms, transcription factors and microRNAs are the major families of gene regulators. Recent studies have suggested that these two kinds of regulators share similar regulatory logics and participate in cooperative activities in the gene regulatory network; however, their combinational regulatory effects and preferences on the protein interaction network remain unclear. Methods: In this study, we constructed a global human gene regulatory network comprising both transcriptional and post-transcriptional regulatory relationships, and integrated the protein interactome into this network. We then screened the integrated network for four types of regulatory motifs: single-regulation, co regulation, crosstalk, and independent, and investigated their topological properties in the protein interaction network. Results: Among the four types of network motifs, the crosstalk was found to have the most enriched protein-protein interactions in their downstream regulatory targets. The topological properties of these motifs also revealed that they target crucial proteins in the protein interaction network and may serve important roles of biological functions. Conclusions: Altogether, these results reveal the combinatorial regulatory patterns of transcription factors and microRNAs on the protein interactome, and provide further evidence to suggest the connection between gene regulatory network and protein interaction network.