The role of site accessibility in microRNA target recognition.
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.
Kertesz
Michael
M
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
Iovino
Nicola
N
Unnerstall
Ulrich
U
Gaul
Ulrike
U
Segal
Eran
E
D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D009690:Nucleic Acid Conformation; D012333:RNA, Messenger / Q000378:metabolism; D013816:Thermodynamics
D035683:MicroRNAs; D012333:RNA, Messenger