When circular RNAs meet the genome: CiR-loops as chromatin regulators and disease drivers

R-loops are three-stranded nucleic acid structures consisting of a DNA-RNA hybrid strand and a displaced single-stranded DNA, and represent pervasive chromatin structural features in eukaryotic cells. Although it has long been considered that the RNA substrates of R-loops are linear RNAs, emerging evidence has demonstrated that circular RNAs (circRNAs), a class of covalently closed single-stranded RNAs generated via back-splicing, can also hybridize with genomic DNA to form R-loops. These circRNA-derived R-loops are termed ciR-loops herein. Owing to the exceptional stability of circRNAs relative to their linear counterparts, ciR-loops are more difficult to resolve than those derived from linear RNAs. Consequently, the accumulation of unscheduled or deleterious ciR-loops can more readily interfere with gene transcription and replication, posing greater threats to genomic and transcriptomic integrity. Given that functions and regulatory mechanisms of ciR-loops have gained increasing attention in the field of RNA biology and gene expression, particularly over the past 3 years, a timely and comprehensive review is urgently needed. However, the molecular mechanisms underlying ciR-loop metabolism and hot spots of investigations about ciR-loop-mediated chromatin regulation are yet to be summarized. Here, we provide a systematic review of recent advances in ciR-loop biology, focusing on the diverse mechanisms of their formation and resolution, as well as their molecular and physiological functions.