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Open Access Highly Accessed Research article

Combinatorial network of transcriptional regulation and microRNA regulation in human cancer

Hui Yu12, Kang Tu2, Yi-Jie Wang4, Jun-Zhe Mao4, Lu Xie2*, Yuan-Yuan Li2* and Yi-Xue Li123*

Author Affiliations

1 Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China

2 Shanghai Center for Bioinformation Technology, 100 Qinzhou Road, Shanghai, 200235, People's Republic of China

3 School of Life Science and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China

4 Shanghai High School, 989 Baise Road, Shanghai, 200231, People's Republic of China

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BMC Systems Biology 2012, 6:61  doi:10.1186/1752-0509-6-61

Published: 12 June 2012

Abstract

Background

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.

Results

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.

Conclusions

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.