Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

The biogenesis and emerging roles of circular RNAs

Nature Reviews Molecular Cell Biology volume 17, pages 205–211 (2016)Cite this article

Subjects

Abstract

Circular RNAs (circRNAs) are produced from precursor mRNA (pre-mRNA) back-splicing of thousands of genes in eukaryotes. Although circRNAs are generally expressed at low levels, recent findings have shed new light on their cell type-specific and tissue-specific expression and on the regulation of their biogenesis. Furthermore, the data indicate that circRNAs shape gene expression by titrating microRNAs, regulating transcription and interfering with splicing, thus effectively expanding the diversity and complexity of eukaryotic transcriptomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Circular RNA (circRNA) biogenesis and its regulation.
Figure 2: Possible roles of circular RNAs (circRNAs) in gene regulation.

Similar content being viewed by others

References

  1. Nigro, J. M. et al. Scrambled exons. Cell 64, 607–613 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Cocquerelle, C., Daubersies, P., Majerus, M. A., Kerckaert, J. P. & Bailleul, B. Splicing with inverted order of exons occurs proximal to large introns. EMBO J. 11, 1095–1098 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Capel, B. et al. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73, 1019–1030 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Cocquerelle, C., Mascrez, B., Hetuin, D. & Bailleul, B. Mis-splicing yields circular RNA molecules. FASEB J. 7, 155–160 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Pasman, Z., Been, M. D. & Garcia-Blanco, M. A. Exon circularization in mammalian nuclear extracts. RNA 2, 603–610 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 ONE 7, e30733 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jeck, W. R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 141–157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, X. O. et al. Complementary sequence-mediated exon circularization. Cell 159, 134–147 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Guo, J. U., Agarwal, V., Guo, H. & Bartel, D. P. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15, 409 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Westholm, J. O. et al. Genome-wide analysis of Drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep. 9, 1966–1980 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ivanov, A. et al. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10, 170–177 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Fan, X. et al. Single-cell RNA-seq transcriptome analysis of linear and circular RNAs in mouse preimplantation embryos. Genome Biol. 16, 148 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kelly, S., Greenman, C., Cook, P. R. & Papantonis, A. Exon skipping is correlated with exon circularization. J. Mol. Biol. 427, 2414–2417 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Ashwal-Fluss, R. et al. circRNA biogenesis competes with pre-mRNA splicing. Mol. Cell 56, 55–66 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Liang, D. & Wilusz, J. E. Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 28, 2233–2247 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Starke, S. et al. Exon circularization requires canonical splice signals. Cell Rep. 10, 103–111 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Conn, S. J. et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 160, 1125–1134 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Kramer, M. C. et al. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev. 29, 2168–2182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, Y. et al. Circular intronic long noncoding RNAs. Mol. Cell 51, 792–806 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Li, Z. et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22, 256–264 (2015).

    Article  PubMed  CAS  Google Scholar 

  23. Lukiw, W. J. Circular RNA (circRNA) in Alzheimer's disease (AD). Front. Genet. 4, 307 (2013).

    PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yang, L., Duff, M. O., Graveley, B. R., Carmichael, G. G. & Chen, L. L. Genome-wide characterization of non-polyadenylated RNAs. Genome Biol. 12, R16 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu, T. et al. Transcriptome-wide investigation of circular RNAs in rice. RNA 21, 2076–2087 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, P. L. et al. Circular RNA is expressed across the eukaryotic tree of life. PLoS ONE 9, e90859 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Barrett, S. P., Wang, P. L. & Salzman, J. Circular RNA biogenesis can proceed through an exon-containing lariat precursor. eLife 4, e07540 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Broadbent, K. M. et al. Strand-specific RNA sequencing in Plasmodium falciparum malaria identifies developmentally regulated long non-coding RNA and circular RNA. BMC Genomics 16, 454 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rybak-Wolf, A. et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol. Cell 58, 870–885 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. You, X. et al. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat. Neurosci. 18, 603–610 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, Y. & Wang, Z. Efficient backsplicing produces translatable circular mRNAs. RNA 21, 172–179 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Bentley, D. L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15, 163–175 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Szabo, L. et al. Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol. 16, 126 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Chen, T. et al. ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner. Cell Res. 25, 459–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, C. Y. & Sarnow, P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268, 415–417 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Hansen, T. B. et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 30, 4414–4422 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Denzler, R., Agarwal, V., Stefano, J., Bartel, D. P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Braunschweig, U. et al. Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res. 24, 1774–1786 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gardner, E. J., Nizami, Z. F., Talbot, C. C. Jr & Gall, J. G. Stable intronic sequence RNA (sisRNA), a new class of noncoding RNA from the oocyte nucleus of Xenopus tropicalis. Genes Dev. 26, 2550–2559 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Talhouarne, G. J. & Gall, J. G. Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA 20, 1476–1487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Armakola, M. et al. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat. Genet. 44, 1302–1309 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bahn, J. H. et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin. Chem. 61, 221–230 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Memczak, S., Papavasileiou, P., Peters, O. & Rajewsky, N. Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS ONE 10, e0141214 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Li, Y. et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 25, 981–984 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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. USA 73, 3852–3856 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H. & Schellekens, H. The hepatitis delta (δ) virus possesses a circular RNA. Nature 323, 558–560 (1986).

    Article  CAS  PubMed  Google Scholar 

  50. Flores, R. et al. Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme. RNA Biol. 8, 200–206 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Cote, F. & Perreault, J. P. Peach latent mosaic viroid is locked by a 2′,5′-phosphodiester bond produced by in vitro self-ligation. J. Mol. Biol. 273, 533–543 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Tang, T. H. et al. RNomics in Archaea reveals a further link between splicing of archaeal introns and rRNA processing. Nucleic Acids Res. 30, 921–930 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Danan, M., Schwartz, S., Edelheit, S. & Sorek, R. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res. 40, 3131–3142 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Soma, A. et al. Permuted tRNA genes expressed via a circular RNA intermediate in Cyanidioschyzon merolae. Science 318, 450–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Grabowski, P. J., Zaug, A. J. & Cech, T. R. The intervening sequence of the ribosomal RNA precursor is converted to a circular RNA in isolated nuclei of Tetrahymena. Cell 23, 467–476 (1981).

    Article  CAS  PubMed  Google Scholar 

  56. Cech, T. R. Self-splicing of group I introns. Annu. Rev. Biochem. 59, 543–568 (1990).

    Article  CAS  PubMed  Google Scholar 

  57. Li-Pook-Than, J. & Bonen, L. Multiple physical forms of excised group II intron RNAs in wheat mitochondria. Nucleic Acids Res. 34, 2782–2790 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Molina-Sanchez, M. D., Martinez-Abarca, F. & Toro, N. Excision of the Sinorhizobium meliloti group II intron RmInt1 as circles in vivo. J. Biol. Chem. 281, 28737–28744 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Abelson, J., Trotta, C. R. & Li, H. tRNA splicing. J. Biol. Chem. 273, 12685–12688 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Salgia, S. R., Singh, S. K., Gurha, P. & Gupta, R. Two reactions of Haloferax volcanii RNA splicing enzymes: joining of exons and circularization of introns. RNA 9, 319–330 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lu, Z. et al. Metazoan tRNA introns generate stable circular RNAs in vivo. RNA 21, 1554–1565 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bachmayr-Heyda, A. et al. Correlation of circular RNA abundance with proliferation—exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci. Rep. 5, 8057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yap, K. L. et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol. Cell 38, 662–674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author is grateful to Li Yang for discussions. This work was supported by grants 91440202 and 31322018 from the Natural Science Foundation of China (NSFC), and XDA01010206 from the Chinese Academy of Sciences (CAS).

Author information

Authors and Affiliations

  1. Ling-Ling Chen is at the State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, 200031 Shanghai, China.,

    Ling-Ling Chen

Authors
  1. Ling-Ling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ling-Ling Chen.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17, 205–211 (2016). https://doi.org/10.1038/nrm.2015.32

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2015.32

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing