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The role of site accessibility in microRNA target recognition

Nature Genetics volume 39, pages 12781284 (2007) | Download Citation

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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.

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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

    • Michael Kertesz
    • , Nicola Iovino
    • , Ulrike Gaul
    •  & Eran Segal

    These authors contributed equally to this work.

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, New York 10021, USA.

    • Nicola Iovino
    • , Ulrich Unnerstall
    •  & Ulrike Gaul

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Corresponding authors

Correspondence to Ulrike Gaul or Eran Segal.

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–7, Supplementary Tables 1–4

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DOI

https://doi.org/10.1038/ng2135

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