Abstract
It has recently been reported that thousands of covalently linked circular RNAs (circRNAs) are expressed from human genomes. circRNAs emerge during RNA splicing. circRNAs are circularized in a reaction termed “backsplicing,” whereby the spliceosome fuses a splice donor site in a downstream exon to a splice acceptor site in an upstream exon. Although a young field of research, first studies indicate that backsplicing is not an erroneous reaction of the spliceosome. Instead, circRNAs are produced in cells with high cell-type specificity and can exert biologically meaningful and specific functions. These observations and the finding that circRNAs are stable against exonucleolytic decay are raising the question whether circRNAs may be relevant as therapeutic agents and targets. In this review, we start out with a short introduction into classification, biogenesis and general molecular mechanisms of circRNAs. We then describe reports, where manipulating circRNA abundance has been shown to have therapeutic value in animal disease models in vivo, with a focus on cardiovascular disease (CVD). Starting from existing approaches, we outline particular challenges and opportunities for future circRNA-based therapeutic approaches that exploit stability and molecular effector functions of native circRNAs. We end with considerations which designer functions could be engineered into artificial therapeutic circular RNAs.
Highlights
CircRNAs are 3 -5 covalently closed RNA rings, and circRNAs do not display 5 Cap or 3 poly(A) tails. 3–10 different circRNA isoforms are formed per host gene, resulting in tens of thousands of distinct circRNAs per cell type (Jeck et al, 2013; Memczak et al, 2013; Salzman et al, 2013; Guo et al, 2014; Westholm et al, 2014; Zhang et al, 2014; Ivanov et al, 2015; Rybak-Wolf et al, 2015). circRNAs are produced by the process of splicing, and circularization occurs using conventional splice sites mostly at annotated exon boundaries (Starke et al, 2015; Szabo et al, 2015)
Analyses in different animal models have consistently shown that forward splicing is dominant, but backsplicing frequency is favored depending on context and availability of splice sites (Salzman et al, 2012; Ashwal-Fluss et al, 2014; Guo et al, 2014; Liang and Wilusz, 2014; Starke et al, 2015; Zhang et al, 2016; Liang et al, 2017): Two fundamentally different modes of circRNA biogenesis have been described: (1) Cotranscriptional backsplicing within the linear pre-mRNA and (2) Posttranscriptional backsplicing from within already excised exon(s)- and intron(s)-containing lariats (Barrett et al, 2015; Zhang et al, 2016)
Most DNA constructs that have been successfully employed for circRNA overexpression in cells used parts of native introns with inverted repeats (IRs) therein, or employ sequences artificially cloned in reverse complementary orientation adjacent to circularizing exons (Figure 1A) (Zhang et al, 2014; Kramer et al, 2015; Starke et al, 2015)
Summary
CircRNAs are produced in cells with high cell-type specificity and can exert biologically meaningful and specific functions. These observations and the finding that circRNAs are stable against exonucleolytic decay are raising the question whether circRNAs may be relevant as therapeutic agents and targets. We start out with a short introduction into classification, biogenesis and general molecular mechanisms of circRNAs. We describe reports, where manipulating circRNA abundance has been shown to have therapeutic value in animal disease models in vivo, with a focus on cardiovascular disease (CVD). Starting from existing approaches, we outline particular challenges and opportunities for future circRNA-based therapeutic approaches that exploit stability and molecular effector functions of native circRNAs. We end with considerations which designer functions could be engineered into artificial therapeutic circular RNAs
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