Abstract
BackgroundIn 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.ResultsHere 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.ConclusionsMTBs 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1178) contains supplementary material, which is available to authorized users.
Highlights
In the competing endogenous RNA hypothesis, different transcripts communicate through a competition for their common targeting microRNAs
Our results suggest widespread expression buffering between messenger RNA (mRNA) commonly targeted by the same miRNAs, which is in line with the competing endogenous RNA (ceRNA) hypothesis
Expression of miRNAs and mRNAs in the same microRNA-target biclusters (MTBs) are significantly more anti-correlated than general miRNA-target pairs As a way to check whether the MTBs we identified represent modules with biological relevance, we examined the expression levels of the miRNAs and mRNAs in human cell lines obtained from RNA-seq experiments performed by the ENCODE Project Consortium [23,24]
Summary
In the competing endogenous RNA (ceRNA) hypothesis, different transcripts communicate through a competition for their common targeting microRNAs (miRNAs). It remains unclear to what extent gene expression levels are regulated by ceRNA in general. If the expression level of an mRNA is decreased, more copies of its targeting miRNAs will become available. Different transcripts (mRNAs and other non-coding RNAs) with MREs of the same miRNA may compete for the finite copies of the miRNA in a cell. This backregulation mechanism and its in vivo functional roles have been coined the competing endogenous RNA (ceRNA) hypothesis [8]
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