Skip to main content

Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency

  • Chapter
  • First Online:
Dissecting Regulatory Interactions of RNA and Protein

Part of the book series: Springer Theses ((Springer Theses))

Abstract

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse, and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. D.P. Bartel, Micrornas: target recognition and regulatory functions. Cell 136(2), 215–233 (2009)

    Article  Google Scholar 

  2. M. Cabili, C. Trapnell, L. Goff, M. Koziol, B. Tazon-Vega, A. Regev, J.L. Rinn, Integrative annotation of human large intergenic noncoding rnas reveals global properties and specific subclasses. Genes. Dev. 25(18), 1915–1927 (2011)

    Article  Google Scholar 

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

    Article  Google Scholar 

  4. M.R. Chacón, A.I. Navarro, G. Cuesto, I. del Pino, R. Scott, M. Morales, B. Rico, Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth. Development 139(17), 3200–3210 (2012). (Cambridge)

    Google Scholar 

  5. M. Danan, S. Schwartz, S. Edelheit, R. Sorek, Transcriptome-wide discovery of circular rnas in archaea. Nucleic Acids Res. 40(7), 3131–3142 (2012)

    Article  Google Scholar 

  6. J.G. Doench, P.A. Sharp, Specificity of microrna target selection in translational repression. Genes Dev. 18(5), 504–511 (2004)

    Article  Google Scholar 

  7. E.J. Dropcho, Y.-T. Chen, J.B. Posner, L.J. Old, Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc. Nat. Acad. Sci. U.S.A. 84(13), 4552–4556 (1987)

    Article  Google Scholar 

  8. P.J. Grabowski, A.J. Zaug, T.R. Cech, The intervening sequence of the ribosomal rna precursor is converted to a circular rna in isolated nuclei of tetrahymena. Cell 23(2), 467–476 (1981)

    Article  Google Scholar 

  9. M. Hafner, M. Landthaler, L. Burger, M. Khorshid, J. Hausser, P. Berninger, A. Rothballer, M. Ascano Jr, A.-C. Jungkamp, M. Munschauer, A. Ulrich, G.S. Wardle, S. Dewell, M. Zavolan, T. Tuschl, Transcriptome-wide identification of rna-binding protein and microrna target sites by par-clip. Cell 141(1), 129–141 (2010)

    Article  Google Scholar 

  10. B.T. Hansen, E.D. Wiklund, J.B. Bramsen, S.B. Villadsen, A.L. Statham, S.J. Clark, J. Kjems, Mirna-dependent gene silencing involving ago2-mediated cleavage of a circular antisense rna. EMBO J. 30(21), 4414–4422 (2011)

    Article  Google Scholar 

  11. R. Huang, M. Jaritz, P. Guenzl, I. Vlatkovic, A. Sommer, I.M. Tamir, H. Marks, T. Klampfl, R. Kralovics, H.G. Stunnenberg, D.P. Barlow, F.M. Pauler, An RNA-seq strategy to detect the complete coding and non-coding transcriptome including full-length imprinted macro ncrnas. PLoS One 6(11), e27288 (2011)

    Article  Google Scholar 

  12. F. Causeret, T. Jacobs, Y.V. Nishimura, M. Terao, A. Norman, M. Hoshino, M. Nikolić, Localized activation of p21-activated kinase controls neuronal polarity and morphology. J. Neurosci. 27(32), 8604–8615 (2007)

    Article  Google Scholar 

  13. M. Kapsimali, W.P. Kloosterman, E. de Bruijn, F. Rosa, R.H.A. Plasterk, S.W. Wilson, MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol. 8(8), R173 (2007)

    Article  Google Scholar 

  14. M.H. Kaufman, J.B.L. Bard, The Anatomical Basis of Mouse, Development (1999)

    Google Scholar 

  15. W.J. Kent, Blat-the blast-like alignment tool. Genome Res. 12(4), 656–664 (2002)

    Article  MathSciNet  Google Scholar 

  16. P. Landgraf, M. Rusu, R. Sheridan, A. Sewer, N. Iovino, A. Aravin, S. Pfeffer, A. Rice, A.O. Kamphorst, M. Landthaler, C. Lin, N.D. Socci, L. Hermida, V. Fulci, S. Chiaretti, A mammalian microrna expression atlas based on small rna library sequencing. Cell 129(7), 1401–1414 (2007)

    Article  Google Scholar 

  17. S. Memczak, M. Jens, A. Elefsinioti, F. Torti, J. Krueger, A. Rybak, L. Maier, S.D. Mackowiak, L.H. Gregersen, M. Munschauer, et al., Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, (2013)

    Google Scholar 

  18. K.D. Pruitt, T. Tatusova, D.R. Maglott, NCBI Reference Sequence (RefSeq): A curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 33, D501–D504 (2005)

    Article  Google Scholar 

  19. C. Salzman, P.L. Gawad, Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 7(2), e30733 (2012)

    Article  Google Scholar 

  20. U. Schambra, Prenatal Mouse Brain Atlas (2008)

    Google Scholar 

  21. G. Shaw, S. Morse, M. Ararat, F.L. Graham, Preferential transformation of human neuronal cells by human adenoviruses and the origin of hek 293 cells. FASEB J. Official Publ. Fed. Am. Soc. Exp. Biol. 16(8), 869–871 (2002)

    Google Scholar 

  22. H. Suzuki, Y. Zuo, J. Wang, M.Q. Zhang, A. Malhotra, A. Mayeda, Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res. 34(8), e63 (2006)

    Article  Google Scholar 

  23. C. Trapnell, L. Pachter, S.L. Salzberg, Tophat: discovering splice junctions with rna-seq. Bioinformatics 25(9), 1105–1111 (2009)

    Article  Google Scholar 

  24. C. Trapnell, B.A. Williams, G. Pertea, A. Mortazavi, Transcript assembly and quantification by rna-seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28(5), 511–515 (2010)

    Article  Google Scholar 

  25. A.P. Vivancos, M. Güell, J.C. Dohm, L. Serrano, H. Himmelbauer, Strand-specific deep sequencing of the transcriptome. Genome Res. 20(7), 989–999 (2010)

    Article  Google Scholar 

  26. phillip d zamore, william e salomon, C fabián flores-jasso, Argonaute divides its rna guide into domains with distinct functions and rna-binding properties. Cell 151(5), 1055–1067 (2012)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marvin Jens .

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Jens, M. (2014). Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency. In: Dissecting Regulatory Interactions of RNA and Protein. Springer Theses. Springer, Cham. https://doi.org/10.1007/978-3-319-07082-7_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-07082-7_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-07081-0

  • Online ISBN: 978-3-319-07082-7

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics