The emerging landscape of circular RNA in life processes

Abstract

Circular RNAs (circRNAs) are a novel class of non-coding RNA that assumes a covalently closed continuous conformation. CircRNAs were previously thought to be the byproducts of splicing errors caused by low abundance and the technological limitations. With the recent development of high-throughput sequencing technology, numerous circRNAs have been discovered in many species. Recent studies have revealed that circRNAs are stable and widely expressed, and often exhibit cell type-specific or tissue-specific expression. Most circRNAs can be generated from exons, introns, or both. Remarkably, emerging evidence indicates that some circRNAs can serve as microRNA (miRNA) sponges, regulate transcription or splicing, and can interact with RNA binding proteins (RBPs). Moreover, circRNAs have been reported to play essential roles in myriad life processes, such as aging, insulin secretion, tissue development, atherosclerotic vascular disease risk, cardiac hypertrophy and cancer. Although circRNAs are ancient molecules, they represent a newly appreciated form of noncoding RNA and as such have great potential implications in clinical and research fields. Here, we review the current understanding of circRNA classification, function and significance in physiological and pathological processes. We believe that future research will increase our understanding of the regulation and function of these novel molecules.

Keywords: Backsplicing; circular RNA; competitive endogenous RNA; microRNA sponge; transcriptional regulation; transcriptome.

Figure 1.

Schematic presentation of circRNA classification. (A) Sense or exonic, when overlapping one or more exons of the linear transcript on the same strand. (B) Intronic, when arising from an intron of the linear transcript in either sense or antisense orientation. (C) Antisense, when overlapping one or more exons of the linear transcript, as they transcribe from the opposite strand. (D) Bidirectional or intragenic, when transcribing from same gene locus of the linear transcript, but in close genomic proximity within 1 kb and not classified into ‘sense’ and ‘intronic’. (E) Intergenic, when it locates outside at least 1kb away from known gene locus.

Figure 2.

Biological functions of circular RNAs. CircRNAs contain miRNA binding sites to act as competitive endogenous RNA. CircRNAs sequester miRNAs from binding mRNA targets. EIciRNAs can enhance gene transcription via interacting with U1 snRNP and RNA Polymerase II in the promoter region of the host gene. GU-rich sequences near the 5’ splice site (red box) and C-rich sequences near branch point (purple box) are minimally sufficient for ciRNA formation. The stable ciRNA binds to elongating RNA Pol II and promotes transcription. CircRNA biogenesis competes with linear splicing. Circularization and splicing compete against each other to keep the transcripts dynamic balance. CircRNA formation act as ‘mRNA trap’ to make linear transcripts untranslated by sequestering the translation start site or break the integrity of mature linear RNA. CircRNAs can also function as RNA binding protein (RBP) sponge to interact with RBPs, such as MBL, p21 and CDK2.