Combinatorial network of transcriptional regulation and microRNA regulation in human cancer.
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.
Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Hui
H
Yu
Kang
K
Tu
Yi-Jie
YJ
Wang
Jun-Zhe
JZ
Mao
Lu
L
Xie
Yuan-Yuan
YY
Li
Yi-Xue
YX
Li
D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D005818:Genetic Engineering; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology; D014158:Transcription, Genetic / Q000235:genetics*
C542541:MIRN106 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human