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Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.

ABSTRACT: BACKGROUND: In the competing endogenous RNA (ceRNA) hypothesis, different transcripts communicate through a competition for their common targeting microRNAs (miRNAs). Individual examples have clearly shown the functional importance of ceRNA in gene regulation and cancer biology. It remains unclear to what extent gene expression levels are regulated by ceRNA in general. One major hurdle to studying this problem is the intertwined connections in miRNA-target networks, which makes it difficult to isolate the effects of individual miRNAs. RESULTS: Here we propose computational methods for decomposing a complex miRNA-target network into largely autonomous modules called microRNA-target biclusters (MTBs). Each MTB contains a relatively small number of densely connected miRNAs and mRNAs with few connections to other miRNAs and mRNAs. Each MTB can thus be individually analyzed with minimal crosstalk with other MTBs. Our approach differs from previous methods for finding modules in miRNA-target networks by not making any pre-assumptions about expression patterns, thereby providing objective information for testing the ceRNA hypothesis. We show that the expression levels of miRNAs and mRNAs in an MTB are significantly more anti-correlated than random miRNA-mRNA pairs and other validated and predicted miRNA-target pairs, demonstrating the biological relevance of MTBs. We further show that there is widespread correlation of expression between mRNAs in same MTBs under a wide variety of parameter settings, and the correlation remains even when co-regulatory effects are controlled for, which suggests potential widespread expression buffering between these mRNAs, which is consistent with the ceRNA hypothesis. Lastly, we also propose a potential use of MTBs in functional annotation of miRNAs. CONCLUSIONS: MTBs can be used to help identify autonomous miRNA-target modules for testing the generality of the ceRNA hypothesis experimentally. The identified modules can also be used to test other properties of miRNA-target networks in general.

SUBMITTER: Yip DK

PROVIDER: S-EPMC4367885 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.

Yip Danny Kit-Sang DK Pang Iris K IK Yip Kevin Y KY

BMC genomics 20141224

<h4>Background</h4>In the competing endogenous RNA (ceRNA) hypothesis, different transcripts communicate through a competition for their common targeting microRNAs (miRNAs). Individual examples have clearly shown the functional importance of ceRNA in gene regulation and cancer biology. It remains unclear to what extent gene expression levels are regulated by ceRNA in general. One major hurdle to studying this problem is the intertwined connections in miRNA-target networks, which makes it difficu ...[more]

PMID: 25539629

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Project description:Colorectal cancer (CRC) is a wide-spread gastrointestinal cancer that is associated with augmented morbidity and mortality, and we do not yet have a deep understanding of its epidemiology and carcinogenicity. The transcriptome can reveal the complexity and heterogeneity of tumors and uncover new biomarkers or treatment options. In this study, we identified messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), round RNAs (circRNAs), and microRNAs (miRNAs) using whole-transcriptome sequencing and generated competing endogenous RNA (ceRNA) modulatory axes. We conducted whole transcriptome sequencing on 10 CRC and para-cancer (CRCP) samples and discovered 2465 differentially expressed (DE) mRNAs (DEmRNAs), 77 DE miRNAs (DEmiRNAs). 2852 DE lncRNAs (DElncRNAs) and 1477 DE circRNAs (DEcircRNAs). In addition, utilizing co-DE analysis, we generated the ceRNA axis. Subsequently, we employed the ceRNA axis to identify essential genes and corresponding associations with lncRNAs, circRNAs, and miRNAs in CRC. ceRNA regulatory network including mRNA-miRNA-lncRNA and mRNA-miRNA-circRNA. These modulatory axes potentially modulate the positive regulation of smooth muscle contraction, melanosome, plasma membrane, integral plasma membrane component and so on. Finally, the results of RNA sequencing (RNA-SEQ) were combined with the TCGA and GEO databases, and the DEGs strongly correlated with the TCGA-COAD overall survival (OS) as estimated by univariate cox and logarithmic rank analyses were cross-analyzed, and the co-upregulated DEGs were screened. Among the many DEs, KPNA2 was chosen for additional analysis. Using invitro experimentations, western blot, CCK8, EdU and other experiments were performed to verify the results. We found siRNA-based KPNA2 depletion reduces bladder cancer cells' viability, migratory, and proliferative activities, which showed that the DEmRNA profiles were comparable to the sequencing information, confirming that the sequencing data were very reliable. These evidences highlight the ceRNA regulatory mechanisms in CRC and will aid future research into the molecular mechanisms behind colorectal cancer prevention and treatment.

Dataset Information

Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.

Publications

Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.

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