The number of biologically relevant microRNA targets has been largely overestimated
Natalia Pinzón1, Blaise Li1, Laura Martinez1, Anna Sergeeva1,5, Jessy Presumey2,3,6, Florence Apparailly2,3,4 and Hervé Seitz1
- Author Affiliations
1Institut de Génétique Humaine, CNRS UPR 1142, 34396 Montpellier, France;
2INSERM, U1183, IRMB, University Hospital St Éloi, 34295 Montpellier, France;
3University of Medicine, 34060 Montpellier, France;
4Clinical Department for Osteoarticular Diseases, University Hospital Lapeyronie, 34295 Montpellier, France
- Author Notes
↵Present addresses: 5MSU, The Museum of Natural History, Moscow, Russia, 119991; 6Children's Hospital, Boston, MA 02115, USA
Corresponding author: herve.seitz@igh.cnrs.fr
Abstract
According to the current view, each microRNA regulates hundreds of genes. Computational tools aim at identifying microRNA targets, usually selecting evolutionarily conserved microRNA binding sites. Here, we provide evidence that such predictions are often biologically irrelevant. Focusing on miR-223-guided repression, we observed that it is often smaller than inter-individual variability in gene expression among wild-type mice, suggesting that most predicted targets are functionally insensitive to that microRNA. Furthermore, we found that human haplo-insufficient genes tend to bear the most highly conserved microRNA binding sites. It thus appears that biological functionality of microRNA binding sites depends on the dose-sensitivity of their host gene and that, conversely, it is unlikely that every predicted microRNA target is dose-sensitive enough to be functionally regulated by microRNAs. We also observed that some mRNAs can efficiently titrate microRNAs, providing a reason for microRNA binding site conservation for inefficiently repressed targets. Finally, many conserved microRNA binding sites are conserved in a microRNA-independent fashion: Sequence elements may be conserved for other reasons, while being fortuitously complementary to microRNAs. Collectively, our data suggest that the role of microRNAs in normal and pathological conditions has been overestimated.
Footnotes
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.205146.116.
Received February 4, 2016. Accepted October 6, 2016.
© 2016 Pinzón et al.; Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
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