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].