Both transcriptional control and microRNA (miRNA) control are critical regulatory mechanisms for cells to direct their destinies. At present, the combinatorial regulatory network composed of transcriptional regulations and post-transcriptional regulations is often constructed through a forward engineering strategy that is based solely on searching of transcriptional factor binding sites or miRNA seed regions in the putative target sequences. If the reverse engineering strategy is integrated with the forward engineering strategy, a more accurate and more specific combinatorial regulatory network will be obtained.
In this work, utilizing both sequence-matching information and parallel expression datasets of miRNAs and mRNAs, we integrated forward engineering with reverse engineering strategies and as a result built a hypothetical combinatorial gene regulatory network in human cancer. The credibility of the regulatory relationships in the network was validated by random permutation procedures and supported by authoritative experimental evidence-based databases. The global and local architecture properties of the combinatorial regulatory network were explored, and the most important tumor-regulating miRNAs and TFs were highlighted from a topological point of view.
By integrating the forward engineering and reverse engineering strategies, we manage to sketch a genome-scale combinatorial gene regulatory network in human cancer, which includes transcriptional regulations and miRNA regulations, allowing systematic study of cancer gene regulation. Our work establishes a pipeline that can be extended to reveal conditional combinatorial regulatory landscapes correlating to specific cellular contexts.