Circular RNAs (circRNAs) in Health and Disease.

Shahnaz Haque,Lorna Harries

doi:10.3390/genes8120353

Abstract

Splicing events do not always produce a linear transcript. Circular RNAs (circRNAs) are a class of RNA that are emerging as key new members of the gene regulatory milieu, which are produced by back-splicing events within genes. In circRNA formation, rather than being spliced in a linear fashion, exons can be circularised by use of the 3′ acceptor splice site of an upstream exon, leading to the formation of a circular RNA species. circRNAs have been demonstrated across species and have the potential to present genetic information in new orientations distinct from their parent transcript. The importance of these RNA players in gene regulation and normal cellular homeostasis is now beginning to be recognised. They have several potential modes of action, from serving as sponges for micro RNAs and RNA binding proteins, to acting as transcriptional regulators. In accordance with an important role in the normal biology of the cell, perturbations of circRNA expression are now being reported in association with disease. Furthermore, the inherent stability of circRNAs conferred by their circular structure and exonuclease resistance, and their expression in blood and other peripheral tissues in association with endosomes and microvesicles, renders them excellent candidates as disease biomarkers. In this review, we explore the state of knowledge on this exciting class of transcripts in regulating gene expression and discuss their emerging role in health and disease.

Highlights

Circular RNAs are an emerging class of RNA species that are present in species as diverse as archaea, flies, and humans [1,2,3,4]. circRNAs in higher organisms are reported to be produced by back-splicing events and can be synthesized from all regions of the genome, deriving mostly from exons but, less commonly, from antisense, intergenic, intragenic, or intronic regions [5]. circRNAs are both spatially and temporally regulated and evidence is emerging that they may have importance in normal development of tissues or organs and in disease pathogenesis
Gene involved in cellular signalling, the profilin 2 (PFN2), and phosphatase and actin regulator 1 (PHACTR1) genes involved in cytoskeletal organisation and the gene encoding the transcription factor paired box 6 (PAX6)
Conclusions circRNAs are a class of non-coding RNAs which appear to regulate the expression of genes by a variety of mechanisms and might have the potential of encoding proteins, the mechanisms of which are not yet completely understood

Summary

Introduction

Circular RNAs (circRNAs) are an emerging class of RNA species that are present in species as diverse as archaea, flies, and humans [1,2,3,4]. circRNAs in higher organisms are reported to be produced by back-splicing events and can be synthesized from all regions of the genome, deriving mostly from exons but, less commonly, from antisense, intergenic, intragenic, or intronic regions [5]. circRNAs are both spatially and temporally regulated and evidence is emerging that they may have importance in normal development of tissues or organs and in disease pathogenesis. Length has been reported to play a part; introns flanking back-spliced tend to be comparatively longer than those flanking non-circularised exons [4]. Repetitive sequences are known to promote back splicing; back-spliced exons that backform spliced exons that form circRNAs are frequently enriched in paired. RNA and a indicated by dashed lines with double arrowheads This may result in the production of a circular linear which lacks the circularised exons. KNIFE can directly back-spliced junctions prior to gene annotations, the other two software systems generate putative retrieve back-spliced junctions prior to gene annotations, the other two software systems generate circRNA sequences post-alignment with the genome or transcriptome [22,23,24]. This approach, the software detects back-spliced sites based on reads mapped alignmentof ofmultiple multiple split thethe genome. RNA [26], species in theshould future.prove useful to researchers interested in these RNA species in the future

Molecular

Translation of circRNAs

Findings

Conclusions