The multilayered complexity of ceRNA crosstalk and competition

Abstract

Recent reports have described an intricate interplay among diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs. These RNA transcripts act as competing endogenous RNAs (ceRNAs) or natural microRNA sponges - they communicate with and co-regulate each other by competing for binding to shared microRNAs, a family of small non-coding RNAs that are important post-transcriptional regulators of gene expression. Understanding this novel RNA crosstalk will lead to significant insight into gene regulatory networks and have implications in human development and disease.

Figure 1. PTEN competing endogenous RNA (ceRNA) network

Validated interactions (grey arrows) between ceRNAs have been reported, shown here with the respective validated microRNAs (miRNAs). Studies have also identified potential ceRNA interactions (blue arrows) based on the respective validated miRNAs. Validated PTEN ceRNAs described in ref. are not included because the specific miRNAs were not identified.

Figure 2. Variable factors that may influence competing endogenous RNA (ceRNA) effectiveness

a, Steady state levels of ceRNA1 (protein-coding region shown in red) and ceRNA2 (protein-coding region shown in blue). Active repression by miRNAs is shown in light grey. b, If expression of ceRNA2 increases, this will increase expression of ceRNA1. c, ceRNA3 has a different subcellular localization from ceRNA1, and may be a less effective ceRNA than ceRNA2. d, Increased expression of the shared miRNA will increase repression of both ceRNA1 and ceRNA2. e, ceRNA4 contains miRNA response elements (MREs, purple and orange) for multiple shared miRNAs, and may be a more effective ceRNA than ceRNA2. f, ceRNA5 contains more MREs than ceRNA2 and may be a more effective ceRNA.