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Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer.

ABSTRACT: BACKGROUND: Lung cancer, especially non-small cell lung cancer, is a leading cause of malignant tumor death worldwide. Understanding the mechanisms employed by the main regulators, such as microRNAs (miRNAs) and transcription factors (TFs), still remains elusive. The patterns of their cooperation and biological functions in the synergistic regulatory network have rarely been studied. RESULTS: Here, we describe the first miRNA-TF synergistic regulation network in human lung cancer. We identified important regulators (MYC, NFKB1, miR-590, and miR-570) and significant miRNA-TF synergistic regulatory motifs by random simulations. The two most significant motifs were the co-regulation of miRNAs and TFs, and TF-mediated cascade regulation. We also developed an algorithm to uncover the biological functions of the human lung cancer miRNA-TF synergistic regulatory network (regulation of apoptosis, cellular protein metabolic process, and cell cycle), and the specific functions of each miRNA-TF synergistic subnetwork. We found that the miR-17 family exerted important effects in the regulation of non-small cell lung cancer, such as in proliferation and cell cycle regulation by targeting the retinoblastoma protein (RB1) and forming a feed forward loop with the E2F1 TF. We proposed a model for the miR-17 family, E2F1, and RB1 to demonstrate their potential roles in the occurrence and development of non-small cell lung cancer. CONCLUSIONS: This work will provide a framework for constructing miRNA-TF synergistic regulatory networks, function analysis in diseases, and identification of the main regulators and regulatory motifs, which will be useful for understanding the putative regulatory motifs involving miRNAs and TFs, and for predicting new targets for cancer studies.

SUBMITTER: Li K

PROVIDER: S-EPMC3843544 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer.

Li Kening K Li Zihui Z Zhao Ning N Xu Yaoqun Y Liu Yongjing Y Zhou Yuanshuai Y Shang Desi D Qiu Fujun F Zhang Rui R Chang Zhiqiang Z Xu Yan Y

BMC systems biology 20131107

<h4>Background</h4>Lung cancer, especially non-small cell lung cancer, is a leading cause of malignant tumor death worldwide. Understanding the mechanisms employed by the main regulators, such as microRNAs (miRNAs) and transcription factors (TFs), still remains elusive. The patterns of their cooperation and biological functions in the synergistic regulatory network have rarely been studied.<h4>Results</h4>Here, we describe the first miRNA-TF synergistic regulation network in human lung cancer. W ...[more]

PMID: 24200043

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Project description:BackgroundMicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.ResultsWe constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.ConclusionThe genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.

Dataset Information

Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer.

Publications

Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer.

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