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Detecting and characterizing circular RNAs
Nature Biotechnologyvolume 32, pages453–461 (2014)Cite this article
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Abstract
Circular RNA transcripts were first identified in the early 1990s but knowledge of these species has remained limited, as their study through traditional methods of RNA analysis has been difficult. Now, novel bioinformatic approaches coupled with biochemical enrichment strategies and deep sequencing have allowed comprehensive studies of circular RNA species. Recent studies have revealed thousands of endogenous circular RNAs in mammalian cells, some of which are highly abundant and evolutionarily conserved. Evidence is emerging that some circRNAs might regulate microRNA (miRNA) function, and roles in transcriptional control have also been suggested. Therefore, study of this class of noncoding RNAs has potential implications for therapeutic and research applications. We believe the key future challenge for the field will be to understand the regulation and function of these unusual molecules.
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References
Nigro, J.M. et al. Scrambled exons.Cell64, 607–613 (1991).
Cocquerelle, C., Mascrez, B., Hétuin, D. & Bailleul, B. Mis-splicing yields circular RNA molecules.FASEB J7, 155–160 (1993).
Kos, A., Dijkema, R., Arnberg, A.C., van der Meide, P.H. & Schellekens, H. The hepatitis delta (delta) virus possesses a circular RNA.Nature323, 558–560 (1986).
Sanger, H.L., Klotz, G., Riesner, D., Gross, H.J. & Kleinschmidt, A.K. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures.Proc. Natl. Acad. Sci. USA73, 3852–3856 (1976).
Hansen, T.B. et al. Natural RNA circles function as efficient microRNA sponges.Nature495, 384–388 (2013).
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency.Nature495, 333–338 (2013).
Zhang, Y. et al. Circular intronic long noncoding RNAs.Mol. Cell51, 792–806 (2013).
Gilbert, W. Why genes in pieces?Nature271, 501 (1978).
Arnberg, A.C., van Ommen, G.J., Grivell, L.A., Van Bruggen, E.F. & Borst, P. Some yeast mitochondrial RNAs are circular.Cell19, 313–319 (1980).
van der Veen, R. et al. Excised group II introns in yeast mitochondria are lariats and can be formed by self-splicing in vitro.Cell44, 225–234 (1986).
Cocquerelle, C., Daubersies, P., Majérus, M.A., Kerckaert, J.P. & Bailleul, B. Splicing with inverted order of exons occurs proximal to large introns.EMBO J.11, 1095–1098 (1992).
Capel, B. et al. Circular transcripts of the testis-determining gene Sry in adult mouse testis.Cell73, 1019–1030 (1993).
Zaphiropoulos, P.G. Differential expression of cytochrome P450 2C24 transcripts in rat kidney and prostate: evidence indicative of alternative and possibly trans splicing events.Biochem. Biophys. Res. Commun.192, 778–786 (1993).
Zaphiropoulos, P.G. Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping.Proc. Natl. Acad. Sci. USA93, 6536–6541 (1996).
Caudevilla, C. et al. Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver.Proc. Natl. Acad. Sci. USA95, 12185–12190 (1998).
Frantz, S.A. et al. Exon repetition in mRNA.Proc. Natl. Acad. Sci. USA96, 5400–5405 (1999).
Surono, A. Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing.Hum. Mol. Genet.8, 493–500 (1999).
Rigatti, R. Exon repetition: a major pathway for processing mRNA of some genes is allele-specific.Nucleic Acids Res.32, 441–446 (2004).
Cocquet, J., Chong, A., Zhang, G. & Veitia, R.A. Reverse transcriptase template switching and false alternative transcripts.Genomics88, 127–131 (2006).
McManus, C.J., Duff, M.O., Eipper-Mains, J. & Graveley, B.R. Global analysis of trans-splicing inDrosophila.Proc. Natl. Acad. Sci. USA107, 12975–12979 (2010).
Tabak, H.F. et al. Discrimination between RNA circles, interlocked RNA circles and lariats using two-dimensional polyacrylamide gel electrophoresis.Nucleic Acids Res.16, 6597–6605 (1988).
Hurowitz, E.H. & Brown, P.O. Genome-wide analysis of mRNA lengths inSaccharomyces cerevisiae.Genome Biol.5, R2 (2003).
Jeck, W.R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA19, 141–157 (2013).
Schindler, C.W., Krolewski, J.J. & Rush, M.G. Selective trapping of circular double-stranded DNA molecules in solidifying agarose.Plasmid7, 263–270 (1982).
Hansen, T.B. et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA.EMBO J.30, 4414–4422 (2011).
Suzuki, H. et al. Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing.Nucleic Acids Res.34, e63 (2006).
Salzman, J., Gawad, C., Wang, P.L., Lacayo, N. & Brown, P.O. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types.PLoS ONE7, e30733 (2012).
Gao, K., Masuda, A., Matsuura, T. & Ohno, K. Human branch point consensus sequence is yUnAy.Nucleic Acids Res.36, 2257–2267 (2008).
Salzman, J., Chen, R.E., Olsen, M.N., Wang, P.L. & Brown, P.O. Cell-type specific features of circular RNA expression.PLoS Genet.9, e1003777 (2013).
Fonseca, N.A., Rung, J., Brazma, A. & Marioni, J.C. Tools for mapping high-throughput sequencing data.Bioinformatics28, 3169–3177 (2012).
Danan, M., Schwartz, S., Edelheit, S. & Sorek, R. Transcriptome-wide discovery of circular RNAs in Archaea.Nucleic Acids Res.40, 3131–3142 (2012).
Wang, K. et al. MapSplice: accurate mapping of RNA-seq reads for splice junction discovery.Nucleic Acids Res.38, e178 (2010).
Brown, J.A., Valenstein, M.L., Yario, T.A., Tycowski, K.T. & Steitz, J.A. Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs.Proc. Natl. Acad. Sci. USA109, 19202–19207 (2012).
Wilusz, J.E. et al. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails.Genes Dev.26, 2392–2407 (2012).
Schwanhäusser, B. et al. Global quantification of mammalian gene expression control.Nature473, 337–342 (2011).
Umekage, S., Uehara, T., Fujita, Y., Suzuki, H. & Kikuchi, Y. inInnovations in Biotechnology (ed. Agbo, E.C.) 75–90.http://cdn.intechopen.com/pdfs/28708/InTech-In_vivo_circular_rna_expression_by_the_permuted_intron_exon_method.pdf (InTech, 2012).
Haupenthal, J., Baehr, C., Kiermayer, S., Zeuzem, S. & Piiper, A. Inhibition of RNAse A family enzymes prevents degradation and loss of silencing activity of siRNAs in serum.Biochem. Pharmacol.71, 702–710 (2006).
Li, X.F. & Lytton, J. A circularized sodium-calcium exchanger exon 2 transcript.J. Biol. Chem.274, 8153–8160 (1999).
Dubin, R.A., Kazmi, M.A. & Ostrer, H. Inverted repeats are necessary for circularization of the mouse testis Sry transcript.Gene167, 245–248 (1995).
Burd, C.E. et al. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk.PLoS Genet.6, e1001233 (2010).
Pasman, Z., Been, M.D. & Garcia-Blanco, M.A. Exon circularization in mammalian nuclear extracts.RNA2, 603–610 (1996).
Ebert, M.S., Neilson, J.R. & Sharp, P.A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells.Nat. Methods4, 721–726 (2007).
Franco-Zorrilla, J.M. et al. Target mimicry provides a new mechanism for regulation of microRNA activity.Nat. Genet.39, 1033–1037 (2007).
Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.Nature465, 1033–1038 (2010).
Hansen, T.B., Kjems, J. & Damgaard, C.K. Circular RNA and miR-7 in Cancer.Cancer Res.73, 5609–5612 (2013).
Liu, Y. et al. Construction of circular miRNA sponges targeting miR-21 or miR-221 and demonstration of their excellent anticancer effects on malignant melanoma cells.Int. J. Biochem. Cell Biol.45, 2643–2650 (2013).
Chao, C.W., Chan, D.C., Kuo, A. & Leder, P. The mouse formin (Fmn) gene: abundant circular RNA transcripts and gene-targeted deletion analysis.Mol. Med.4, 614–628 (1998).
Surono, A. et al. Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing.Hum. Mol. Genet.8, 493–500 (1999).
Gualandi, F. Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion.J. Med. Genet.40, e100 (2003).
Spitali, P. & Aartsma-Rus, A. Splice modulating therapies for human disease.Cell148, 1085–1088 (2012).
Romeo, T. Global regulation by the small RNA-binding protein CsrA and the non-coding RNA molecule CsrB.Mol. Microbiol.29, 1321–1330 (1998).
Chen, C.Y. & Sarnow, P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs.Science268, 415–417 (1995).
Zaphiropoulos, P.G. Exon skipping and circular RNA formation in transcripts of the human cytochrome P-450 2C18 gene in epidermis and of the rat androgen binding protein gene in testis.Mol. Cell. Biol.17, 2985–2993 (1997).
Acknowledgements
The authors would like to acknowledge W. Marzluff for his assistance in preparing this manuscript, as well as funding from the National Institute on Aging, grants F30 AG041567–3 and RO1 AG024379–11.
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Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
William R Jeck & Norman E Sharpless
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Norman E Sharpless
The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Norman E Sharpless
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Jeck, W., Sharpless, N. Detecting and characterizing circular RNAs.Nat Biotechnol32, 453–461 (2014). https://doi.org/10.1038/nbt.2890
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