Circular RNAs in Cardiovascular Disease: An Overview

Abstract

Circular RNA (circRNA), a novel type of endogenous noncoding RNA (ncRNA), has become a research hotspot in recent years. CircRNAs are abundant and stably exist in creatures, and they are found with covalently closed loop structures in which they are quite different from linear RNAs. Nowadays, an increasing number of scientists have demonstrated that circRNAs may have played an essential role in the regulation of gene expression, especially acting as miRNA sponges, and have described the potential mechanisms of several circRNAs in diseases, hinting at their clinical therapeutic values. In this review, the authors summarized the current understandings of the biogenesis and properties of circRNAs and their functions and role as biomarkers in cardiovascular diseases.

Figure 1

Models of circRNA biogenesis: (a) lariat-driven circularization: exon skipping leads to a covalent splice of the splice donor in 3′ end of exon 1 to the splice acceptor in 5′ end of exon 4, which forms a linear product and a lariat structure containing the skipped exons 2 and 3. Then the lariat is joined by spliceosome and the introns are removed to form a circRNA. (b) Intron-pairing-driven circularization: intron 1 and intron 3, which contain complementary sequence motifs, lead to close proximity through direct base-pairing and form a linear RNA and a circular structure. The splicing of the two introns produces a circRNA (exon-only circRNA), while the generation of an EIciRNA (intron-retaining circRNA) is caused by the presence of a retained intron. (c) Circular intronic RNAs: the existence of 7 nt GU-rich element near exon 1 (yellow box) and 11 nt C-rich element near exon 2 (orange box) makes it possible for an intron to escape debranching when the intron lariat is produced from the splicing reaction. (d) RNA binding proteins (RBPs) driven circularization: the interaction between RBPs (Y-shape) can bind to sequence motifs and bring two flanking introns close together. Then the introns are removed to form a circRNA.

Figure 2

A model of the generation of circular Mbl (circMbl) and MBL: CircMbl is derived from the mbl locus and has conserved binding sites for the MBL protein in the flanking intronic sequences, so it can bind MBL protein. Besides, BML levels can strongly affect the splicing process when mbl pre-mRNA produces mbl mRNA and circMbl. When the level of MBL is high, mbl pre-mRNA produces less mbl mRNA and more circMbl. Less mbl mRNA generates less MBL and more circMbl binds to more MBL, so that MBL level decreases. (+) represents promotion while (−) represents inhibition in this figure, and vice versa.

Figure 3

Model of circRNA regulating the expression of a parental gene: (a) CiRNAs come from lariat introns that escape debranching. CiRNA can bind to RNA polymerase II (RNA pol II) and function in the promoter region of genes. (b) EIciRNA can interact with the U1 snRNP (small nuclear ribonucleoprotein) via specific RNA-RNA interaction between U1 snRNP and EIciRNA to form EIciRNA-U1 snRNP complexes, and the complexes will recruit RNA pol II to the promoter to stimulate host gene expression.