The Expanding Repertoire of Circular RNAs

Abstract

In recent years, reports suggesting a process of exon shuffling and the generation of circular RNAs have not gained wide support because they are inconsistent with the established dogma of linear exon splicing. This debate has now come full circle with evidence proving more definitively the existence of circular RNAs in two recent articles published in the 21 March issue of Nature. These articles describe an abundance of examples of circular RNAs in humans, mice, and Caenorhabditis elegans as well as a plausible mechanism for the function of at least some of these as “microRNA sponges” within a cell.1,2 A microRNA (miRNA) sponge is a sequence that sequesters the available pool of a given miRNA so as to reduce its capacity to act on target genes. However, there is as yet relatively little information on the role that these circular RNAs play in cellular homeostasis or disease, such that one might question why these findings deserve the attention of readers of Molecular Therapy. One might have asked similar questions in the 1990s following the discovery of miRNAs, small interfering RNAs (siRNAs), and RNA interference (RNAi). Although miRNA pathways were once thought to be limited to plants and invertebrates, their importance in normal human development and disease becomes more apparent on almost a weekly basis. Moreover, delivery of short duplex siRNAs or DNA templates capable of producing RNA hairpins that are processed into siRNAs—eliciting robust RNAi-induced gene knockdown and RNAi-based therapies—is now in advanced clinical trials.3,4,5 It is not too much of a stretch to speculate that manipulating endogenous circular RNAs will someday provide novel approaches to treat human disease.