Network Approaches to Study Endogenous RNA Competition and Its Impact on Tissue-Specific microRNA Functions

Abstract

microRNAs are small non-coding RNAs that play a key role in regulating gene expression. These molecules exert their function through sequence complementarity with microRNA responsive elements and are typically located in the 3' untranslated region of mRNAs, negatively regulating expression. Even though the relevant role of miRNA-dependent regulation is broadly recognized, the principles governing their ability to lead to specific functional outcomes in distinct cell types are still not well understood. In recent years, an intriguing hypothesis proposed that miRNA-responsive elements act as communication links between different RNA species, making the investigation of microRNA function even more complex than previously thought. The competing endogenous RNA hypothesis suggests the presence of a new level of regulation, whereby a specific RNA transcript can indirectly influence the abundance of other transcripts by limiting the availability of a common miRNA, acting as a "molecular sponge". Since this idea has been proposed, several studies have tried to pinpoint the interaction networks that have been established between different RNA species and whether they contribute to normal cell function and disease. The focus of this review is to highlight recent developments and achievements made towards the process of characterizing competing endogenous RNA networks and their role in cellular function.

Keywords: ceRNA networks; microRNAs; post-transcriptional regulation.

Figure 1

The competing endogenous RNA hypothesis. LncRNAs, circRNAs, and mRNAs can all co-exist in a given cellular context and form complex interaction networks. The type of molecules, their abundance, and presence and number of different microRNA responsive elements (MREs) with varying affinities for specific miRNA sequences can influence the way they interact and form competing endogenous RNA (ceRNA) networks. (A). The role of miRNAs in gene expression regulation is a well-studied mechanism that predominantly occurs through the binding of the seed sequence (nt 2–7) to a complementary MRE that is present in the 3′ UTR of mRNAs, leading to translational repression and/or degradation. However, other RNA molecules are able to interact with miRNAs and titrate their abundance, thus establishing a crosstalk interaction with other potential target molecules. Of note, these molecules often have MREs for many miRNAs, whereas each miRNA can usually target hundreds of different molecules. (B). In a situation where miRNAs are less abundant than a single ceRNA species, they may be sequestered and unable to interact with other targets. (C). When miRNAs are more abundant than the population of target RNA molecules, they are able to bind all of the targets, and some free miRNA may still exist in that context. (D). Complex ceRNA network interactions are more likely to happen when miRNAs and their corresponding MREs are present at similar concentrations. ceRNAs are able to influence the abundance of other RNA molecules that share the same MRE through the titration of free miRNAs. The amount of shared MREs directly influences the strength of crosstalk [50].