An intriguing RNA species—perspectives of circularized RNA

Abstract

Circular RNAs (circRNAs), a kind of covalently closed RNA molecule, were used to be considered a type of byproducts of mis-splicing events and were discovered sporadically due to the technological limits in the early years. With the great technological progress such as high-throughput next-generation sequencing, numerous circRNAs have recently been detected in many species. CircRNAs were expressed in a spatio-temporally specific manner, suggesting their regulatory functional potentials were overlooked previously. Intriguingly, some circRNAs were indeed found with critical physiological functions in certain circumstances. CircRNAs have a more stable molecular structure that can resist to exoribonuclease comparing to those linear ones, and their molecular functions include microRNA sponge, regulatory roles in transcription, mRNA traps that compete with linear splicing, templates for translation and possibly other presently unknown roles. Here, we review the discovery and characterization of circRNAs, the origination and formation mechanism, the physiological functions and the molecular roles, along with the methods for detection of circRNAs. We further look into the future and propose key questions to be answered for these magical RNA molecules.

Keywords

circular RNA / back splice / gene regulation

References

[1] Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56:55–66

[2] Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379

[3] Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE (2010) Expression of linear and novel circular forms of an INK4/ARFassociated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 6:e1001233

[4] Caldas C, So CW, MacGregor A, Ford AM, McDonald B, Chan LC, Wiedemann LM (1998) Exon scrambling of MLL transcripts occur commonly and mimic partial genomic duplication of the gene. Gene 208:167–176

[5] Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P, Goodfellow P, Lovell-Badge R (1993) Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73:1019–1030

[6] Chao CW, Chan DC, Kuo A, Leder P (1998) The mouse forming (Fmn) gene: abundant circular RNA transcripts and genetargeted deletion analysis. Mol Med 4:614–628

[7] Chen CY, Sarnow P (1995) Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268:415–417

[8] Cocquerelle C, Daubersies P, Majerus MA, Kerckaert JP, Bailleul B (1992) Splicing with inverted order of exons occurs proximal to large introns. EMBO J 11:1095–1098

[9] Cocquerelle C, Mascrez B, Hétuin D, Bailleul B (1993) Mis-splicing yields circular RNA molecules. FASEB J 7:155

[10] Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ (2015) The RNA binding protein quaking regulates formation of circRNAs. Cell 160:1125–1134

[11] Danan M, Schwartz S, Edelheit S, Sorek R (2012) Transcriptomewide discovery of circular RNAs in Archaea. Nucleic Acids Res 40:3131–3142

[12] de la Mata M (2003) A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell 2:525–532

[13] Dixon RJ (2005) A genome-wide survey demonstrates widespread non-linear mRNA in expressed sequences from multiple species. Nucleic Acids Res 33:5904–5913

[14] Dolci S, Grimaldi P, Geremia R, Pesce M, Rossi P (1997) Identification of a promoter region generating Sry circular transcripts both in germ cells from male adult mice and in male mouse embryonal gonads. Biol Reprod 57:1128–1135

[15] Flores R, Gago-Zachert S, Serra P, Sanjuan R, Elena SF (2014) Viroids: survivors from the RNA world? Annu Rev Microbiol 68:395–414

[16] Gao Y, Wang J, Zhao F (2015) CIRI: an efficient and unbiased algorithm for de novo circular RNA identification. Genome Biol 16:4

[17] Ghosal S, Das S, Sen R, Basak P, Chakrabarti J (2013) Circ2Traits: a comprehensive database for circular RNA potentially associated with disease and traits. Front Genet 4:283

[18] Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL, Clark SJ, Kjems J (2011) miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J 30:4414–4422

[19] Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388

[20] Houseley JM, Garcia-Casado Z, Pascual M, Paricio N, O’Dell KMC, Monckton DG, Artero RD (2006) Noncanonical RNAs from transcripts of the Drosophila muscleblind Gene. J Hered 97:253–260

[21] Hsu MT, Coca-Prados M (1979) Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature 280:339–340

[22] Ip JY, Schmidt D, Pan Q, Ramani AK, Fraser AG, Odom DT, Blencowe BJ (2011) Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res 21:390–401

[23] Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32:453–461

[24] Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19:141–157

[25] Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM (2009) Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci USA 106:13052–13057

[26] Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH, Wilson SW (2007) MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol 8:R173

[27] Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee J, Fine H, Chiocca EA, Lawler S (2008) microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 68:3566–3572

[28] Keren H, Lev-Maor G, Ast G (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11:345–355

[29] Khodor YL, Rodriguez J, Abruzzi KC, Tang CHA, Marr MT, Rosbash M (2011) Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in Drosophila. Genes Dev 23:2502–2512

[30] Kim D, Salzberg SL (2011) TopHat-Fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol 12:R72

[31] Kos A, Dijkema R, Arnberg AC, van der Meide PH, Schellekens H (1986) The hepatitis delta (delta) virus possesses a circular RNA. Nature 323:558–560

[32] Kramer A (1996) The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem 65:367–409

[33] Li XF, Lytton J (1999) A circularized sodium-calcium exchanger exon 2 transcript. J Biol Chem 274:8153–8160

[34] Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L (2015) Exon–intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22:256–264

[35] Mayer A, Mosler G, Just W, Pilgrim C, Reisert I (2000) Developmental profile of Sry transcripts in mouse brain. Neurogenetics 3:25–30

[36] Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338

[37] Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, Kinzler KW, Vogelstein B (1991) Scrambled exons. Cell 64:607–613

[38] Perriman R, Ares MJ (1998) Circular mRNA can direct translation of extremely long repeating-sequence proteins in vivo. Rna 4:1047–1054

[39] Price AL, Eskin E, Pevzner PA (2004) Whole-genome analysis of Alu repeat elements reveals complex evolutionary history. Genome Res 14:2245–2252

[40] Roossinck MJ, Sleat D, Palukaitis P (1992) Satellite RNAs of plant viruses: structures and biological effects. Microbiol Rev 56:265–279

[41] Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 7:e30733

[42] Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO (2013) Celltype specific features of circular RNA expression. PLoS Genet 9: e1003777

[43] Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK (1976) Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA 73:3852–3856

[44] Saydam O, Senol O, Wurdinger T, Mizrak A,Ozdener GB , Stemmer-Rachamimov AO, Yi M, Stephens RM, Krichevsky AM, Saydam N (2011) miRNA-7 attenuation in Schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. Cancer Res 71:852–861

[45] Schindler CW, Krolewski JJ, Rush MG (1982) Selective trapping of circular double-stranded DNA molecules in solidifying agarose. Plasmid 3:263–270

[46] Schneider IR (1969) Satellite-like particle of tobacco ringspot virus that resembles tobacco ringspot virus. Science 166:1627–1629

[47] Shao X, Shepelev V, Fedorov A (2006) Bioinformatic analysis of exon repetition, exon scrambling and trans-splicing in humans. Bioinformatics 22:692–698

[48] Surono A, Takeshima Y, Wibawa T, Ikezawa M, Nonaka I, Matsuo M (1999) Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing. Hum Mol Genet 8:493–500

[49] Suzuki H (2006) Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res 34:e63

[50] Tabak HF, Van der Horst G, Smit J, Winter AJ, Mul Y, Groot KM (1988) Discrimination between RNA circles, interlocked RNA circles and lariats using two-dimensional polyacrylamide gel electrophoresis. Nucleic Acids Res 16:6597–6605

[51] Wang Y, Wang Z (2014) Efficient backsplicing produces translatable circular mRNAs. RNA 21:172–179

[52] Wang K, Singh D, Zeng Z, Coleman SJ, Huang Y, Savich GL, He X, Mieczkowski P, Grimm SA, Perou CM (2010) MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res 38:e178

[53] Wang Y, Liu J, Liu C, Naji A, Stoffers DA (2013) MicroRNA-7 regulates the mTOR pathway and proliferation in adult pancreatic beta-cells. Diabetes 62:887–895

[54] Wang PL, Bao Y, Yee MC, Barrett SP, Hogan GJ, Olsen MN, Dinneny JR, Brown PO, Salzman J (2014) Circular RNA is expressed across the eukaryotic tree of life. PLoS One 9:e90859

[55] Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

[56] Webster RJ, Giles KM, Price KJ, Zhang PM, Mattick JS, Leedman PJ (2009) Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. J Biol Chem 284:5731–5741

[57] You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C,Quedenau C (2015) Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 18:603–610

[58] Zaphiropoulos PG (1996) Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. Proc Natl Acad Sci USA 93:6536–6541

[59] Zaphiropoulos PG (1997) 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

[60] Zhang XO, Wang HB, Zhang Y, Lu X, Chen LL, Yang L (2014) Complementary sequence-mediated exon circularization. Cell 1:134–147

[61] Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL (2013) Circular intronic long noncoding RNAs. Mol Cell 51:792–806

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