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.

  • Letter
  • Published:

The role of site accessibility in microRNA target recognition

Nature Genetics volume 39, pages 1278–1284 (2007)Cite this article

Abstract

MicroRNAs are key regulators of gene expression1,2,3,4, but the precise mechanisms underlying their interaction with their mRNA targets are still poorly understood. Here, we systematically investigate the role of target-site accessibility, as determined by base-pairing interactions within the mRNA, in microRNA target recognition. We experimentally show that mutations diminishing target accessibility substantially reduce microRNA-mediated translational repression, with effects comparable to those of mutations that disrupt sequence complementarity. We devise a parameter-free model for microRNA-target interaction that computes the difference between the free energy gained from the formation of the microRNA-target duplex and the energetic cost of unpairing the target to make it accessible to the microRNA. This model explains the variability in our experiments, predicts validated targets more accurately than existing algorithms, and shows that genomes accommodate site accessibility by preferentially positioning targets in highly accessible regions. Our study thus demonstrates that target accessibility is a critical factor in microRNA function.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Role of microRNA target-site accessibility in microRNA-mediated repression.
Figure 2: Our microRNA-target interaction model explains variability in target strength due to differences in accessibility.
Figure 3: Our model predicts microRNA-target interactions across a wide range of target types.
Figure 4: Our model accurately predicts previously published microRNA-target interactions.
Figure 5: MicroRNA targets in animal genomes are preferentially located in regions of high accessibility.

Similar content being viewed by others

References

  1. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Carthew, R.W. Gene regulation by microRNAs. Curr. Opin. Genet. Dev. 16, 203–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Esquela-Kerscher, A. & Slack, F.J. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Bartel, D.P. & Chen, C.Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat. Rev. Genet. 5, 396–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Didiano, D. & Hobert, O. Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat. Struct. Mol. Biol. 13, 849–851 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Enright, A.J. et al. MicroRNA targets in Drosophila. Genome Biol. 5, R1 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lewis, B.P., Shih, I.H., Jones-Rhoades, M.W., Bartel, D.P. & Burge, C.B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Stark, A., Brennecke, J., Bushati, N., Russell, R.B. & Cohen, S.M. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123, 1133–1146 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Stark, A., Brennecke, J., Russell, R.B. & Cohen, S.M. Identification of Drosophila MicroRNA targets. PLoS Biol. 1, e60 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Grun, D., Wang, Y.L., Langenberger, D., Gunsalus, K.C. & Rajewsky, N. microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput. Biol. 1, e13 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brennecke, J., Stark, A., Russell, R.B. & Cohen, S.M. Principles of microRNA-target recognition. PLoS Biol. 3, e85 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lai, E.C., Tam, B. & Rubin, G.M. Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs. Genes Dev. 19, 1067–1080 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rehmsmeier, M., Steffen, P., Hochsmann, M. & Giegerich, R. Fast and effective prediction of microRNA/target duplexes. RNA 10, 1507–1517 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Zhao, Y. et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1–2. Cell 129, 303–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Vella, M.C., Reinert, K. & Slack, F.J. Architecture of a validated microRNA:target interaction. Chem. Biol. 11, 1619–1623 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Robins, H., Li, Y. & Padgett, R.W. Incorporating structure to predict microRNA targets. Proc. Natl. Acad. Sci. USA 102, 4006–4009 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Long, D. et al. Potent effect of target structure on microRNA function. Nat. Struct. Mol. Biol. 14, 287–294 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Muckstein, U. et al. Thermodynamics of RNA-RNA binding. Bioinformatics 22, 1177–1182 (2006).

    Article  PubMed  Google Scholar 

  21. Leaman, D. et al. Antisense-mediated depletion reveals essential and specific functions of microRNAs in Drosophila development. Cell 121, 1097–1108 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Valencia-Sanchez, M.A., Liu, J., Hannon, G.J. & Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Hofacker, I.L. Vienna RNA secondary structure server. Nucleic Acids Res. 31, 3429–3431 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wiese, K.C. & Hendriks, A. Comparison of P-RnaPredict and mfold–algorithms for RNA secondary structure prediction. Bioinformatics 22, 934–942 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Sontheimer, E.J. Assembly and function of RNA silencing complexes. Nat. Rev. Mol. Cell Biol. 6, 127–138 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Parker, J.S., Roe, S.M. & Barford, D. Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex. Nature 434, 663–666 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ameres, S.L., Martinez, J. & Schroeder, R. Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130, 101–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Haley, B. & Zamore, P.D. Kinetic analysis of the RNAi enzyme complex. Nat. Struct. Mol. Biol. 11, 599–606 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Sethupathy, P., Corda, B. & Hatzigeorgiou, A.G. TarBase: A comprehensive database of experimentally supported animal microRNA targets. RNA 12, 192–197 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rehwinkel, J. et al. Genome-wide analysis of mRNAs regulated by Drosha and Argonaute proteins in Drosophila melanogaster. Mol. Cell. Biol. 26, 2965–2975 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank O. Manor for assistance with genome-wide predictions, Y. Lubling for creating the supplementary website, T. Tuschl and B. Darnell for the use of equipment, and K. O'Donovan and J. Fak for technical assistance. This work was supported by the Israel Science Foundation (M.K., E.S.), a PhD fellowship from the University of Rome “La Sapienza” (N.I.) and the Rockefeller University (U.G.). E.S. is the incumbent of the Soretta and Henry Shapiro career development chair.

Author information

Author notes

  1. Michael Kertesz, Nicola Iovino, Ulrike Gaul and Eran Segal: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, 76100, Israel

    Michael Kertesz & Eran Segal

  2. Laboratory of Developmental Neurogenetics, Rockefeller University, New York, 10021, New York, USA

    Nicola Iovino, Ulrich Unnerstall & Ulrike Gaul

Authors
  1. Michael Kertesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicola Iovino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulrich Unnerstall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrike Gaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eran Segal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ulrike Gaul or Eran Segal.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–7, Supplementary Tables 1–4 (PDF 3917 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kertesz, M., Iovino, N., Unnerstall, U. et al. The role of site accessibility in microRNA target recognition. Nat Genet 39, 1278–1284 (2007). https://doi.org/10.1038/ng2135

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2135

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