Circular RNAs constitute an inherent gene regulatory axis in the mammalian eye and brain

Abstract

Circular RNAs (circRNAs) are being hailed as a newly rediscovered class of covalently closed transcripts that are produced via alternative, noncanonical pre-mRNA back-splicing events. These single-stranded RNA molecules have been identified in organisms ranging from the worm (Cortés-López et al. 2018. BMC Genomics, 19: 8; Ivanov et al. 2015. Cell Rep. 10: 170–177) to higher eukaryotes (Yang et al. 2017. Cell Res. 27: 626–641) to plants (Li et al. 2017. Biochem. Biophys. Res. Commun. 488: 382–386). At present, research on circRNAs is an active area because of their diverse roles in development, health, and diseases. Partly because their circularity makes them resistant to degradation, they hold great promise as unique biomarkers for ocular and central nervous system (CNS) disorders. We believe that further work on their applications could help in developing them as “first-in-class” diagnostics, therapeutics, and prognostic targets for numerous eye conditions. Interestingly, many circRNAs play key roles in transcriptional regulation by acting as miRNAs sponges, meaning that they serve as master regulators of RNA and protein expression. Since the retina is an extension of the brain and is part of the CNS, we highlight the current state of circRNA biogenesis, properties, and function and we review the crucial roles that they play in the eye and the brain. We also discuss their regulatory roles as miRNA sponges, regulation of their parental genes or linear mRNAs, translation into micropeptides or proteins, and responses to cellular stress. We posit that future advances will provide newer insights into the fields of RNA metabolism in general and diseases of the aging eye and brain in particular. Furthermore, in keeping pace with the rapidly evolving discipline of RNA“omics”-centered metabolism and to achieve uniformity among researchers, we recently introduced the term “cromics” (circular ribonucleic acids based omics) (Singh et al. 2018. Exp. Eye Res. 174: 80–92).