RNA Sponges in the Regulation of miRNA Activity
The hypothesis of competing endogenous RNA (ceRNA) molecules, better known as RNA sponges, represents a novel regulatory dimension in translational biology. ceRNAs function as sponges that sequester miRNAs to influence the expression level of other transcripts sharing common miRNA response elements (MREs). RNA molecules of different fates such as non-coding RNAs, circular RNAs, and pseudogenes can compete for miRNA binding due to the presence of similar MREs (Fig. 1.1) (Salmena et al. 2011; Tay et al. 2014). Under particular conditions, RNA molecules with a large number of MREs, such as circular RNA (CDR1as) containing several miR-7 seed matches, can act as a miRNA sponge by efficiently binding and thereby eliminating specific miRNAs from their defined targets (Hansen et al. 2013). In addition, non-coding pseudogenes, such as PTENP1, which contain similar MREs as their ancestral gene (PTEN) is capable to bind and compete for the same miRNAs (Poliseno et al. 2010). Basically, the ceRNA mechanism may only be relevant for miRNAs that target two or more RNA molecules because miRNAs that bind to a single target mRNA are not regulated by ceRNAs (Helwak et al. 2013).
The sponge mechanism of ceRNAs is modulated by various parameters including stability of miRNA expression, large changes in ceRNA expression, accessibility of ceRNA influenced by cellular localization or interaction with RNA-binding proteins, and the efficiency of miRNAs binding to each MRE (Salmena et al. 2011). However, the ceRNA model may not be relevant for all miRNAs and differ between cell types. For instance, the manipulation of miR-122 target abundance in the liver in a physiological and disease setting did not significantly affect gene expression and metabolism in the tissue (Denzler et al. 2014).