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Review
. 2018 Feb 25;3(1):1-11.
doi: 10.1016/j.ncrna.2018.02.002. eCollection 2018 Mar.

Circular RNAs in the cardiovascular system

Clarissa P C Gomes  1 , Antonio Salgado-Somoza  1 , Esther E Creemers  2 , Christoph Dieterich  3 , Mitja Lustrek  4 , Yvan Devaux  1 ; Cardiolinc™ network
Affiliations
Review

Circular RNAs in the cardiovascular system

Clarissa P C Gomes et al. Noncoding RNA Res. .

Erratum in

Abstract

Until recently considered as rare, circular RNAs (circRNAs) are emerging as important regulators of gene expression. They are ubiquitously expressed and represent a novel branch of the family of non-coding RNAs. Recent investigations showed that circRNAs are regulated in the cardiovascular system and participate in its physiological and pathological development. In this review article, we will provide an overview of the role of circRNAs in cardiovascular health and disease. After a description of the biogenesis of circRNAs, we will summarize what is known of the expression, regulation and function of circRNAs in the cardiovascular system. We will then address some technical aspects of circRNAs research, discussing how artificial intelligence may aid in circRNAs research. Finally, the potential of circRNAs as biomarkers of cardiovascular disease will be addressed and directions for future research will be proposed.

Keywords: Artificial intelligence; Biomarker; CRISPR, clustered regularly interspaced short palindromic repeats; CV, cardiovascular; Cardiovascular disease; Cardiovascular system; Circular RNAs; DCM, dilated cardiomyopathy; EMT, epithelial-mesenchymal transition; Non-coding RNAs; RNA-seq, RNA sequencing; RPAD, RNase R treatment followed by polyadenylation and poly(A)+ RNA depletion; RT-qPCR, reverse transcription quantitative polymerase chain reaction; circRNAs, circular RNAs; lncRNAs, long non-coding RNAs; miRNAs, microRNAs; ncRNAs, non-coding RNAs.

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Figures

Fig. 1
Fig. 1
The non-coding RNA family. Non-coding RNAs are classified depending on their size with an arbitrary cut-off of 200 nucleotides. Abbreviations: ncRNAs: noncoding RNAs; lncRNA: long noncoding RNA; eRNA: enhancer RNA; circRNA: circular RNA; rRNA: ribosomal RNA; snRNA: small nuclear RNA; scaRNA: small cajal body-specific RNA; snoRNA: small nucleolar RNA; tiRNA: tRNA-derived stress-induced small RNA; tRNA: transfer RNA; RNAi: RNA interference; siRNA: small interfering RNA; piRNA: piwi-interacting RNA; miRNA: microRNA; rasiRNA: repeat associated small interfering RNA.
Fig. 2
Fig. 2
Biogenesis of circRNAs. The spliceosome machinery, which normally catalyses linear splicing of pre-mRNA, can also perform a back-splicing reaction between two exons, resulting in the formation of a circRNA. Back-splicing uses the same canonical splicing machinery and canonical splice sites as needed for linear splicing. Mechanistically, back-splicing requires that the donor and acceptor site of the back-spliced exons are brought in close proximity to each other, which can be accomplished by direct RNA base-pairing of reverse complementary sequences in the introns flanking the back-spliced exons, or by the interaction of RNA binding proteins (RBPs) that dock on these flanking introns.
Fig. 3
Fig. 3
Functions of circRNAs. a) In the presence of internal ribosomal enter sites and a suitable open reading frame, circRNAs could be translated into proteins. b) Generation of circRNAs by back-splicing of the precursor RNA can lead to a regulation of the linear/circular ratio of the hosting gene. c) CircRNAs can sponge microRNAs to act as a cytoplasmic reservoir of microRNAs. The scavenging of microRNAs removes the repression of target RNAs leading to an increase in their translation (if mRNAs) or activity (lncRNAs). d) CircRNAs can act as a scaffold for cytoplasmic proteins, retain certain transcription factors in the cytoplasm or serve as a vehicle for the transport of these molecules. e) CircRNAs could undergo degradation after being targeted by microRNAs. f) CircRNAs could function as a scaffold for transcription factors leading them to specific locations of the genome or directly interact with the DNA to regulate transcription.
Fig. 4
Fig. 4
Different sequencing strategies to detect back-splicing junctions and to recover the internal structure of circular RNAs.
See this image and copyright information in PMC

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