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The role of site accessibility in microRNA target recognition

Michael Kertesz^1*, Nicola Iovino^2*, Ulrich Unnerstall², Ulrike Gaul^2†& Eran Segal^1†

MicroRNAs are key regulators of gene expression, 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.

Illustration of our ΔΔG score for microRNA-target interactions, computed as the free energy gained by transitioning from the state in which the microRNA and the target are unbound (left), and the state in which the microRNA binds its target (right).

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¹ Dept. of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
² Laboratory of Developmental Neurogenetics, Rockefeller University, New York, NY 10021, USA.
^* These authors contributed equally to this work.
^† These authors contributed equally to this work. Correspondence should be addressed to U.G. or E.S.