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Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family inC. elegans


Subasic, Deni; Brümmer, Anneke; Wu, Yibo; Pinto, Sérgio Morgado; Imig, Jochen; Keller, Martin; Jovanovic, Marko; Lightfoot, Helen Louise; Nasso, Sara; Goetze, Sandra; Brunner, Erich; Hall, Jonathan; Aebersold, Ruedi; Zavolan, Mihaela; Hengartner, Michael O (2015). Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family inC. elegans. Genome Research, 25(11):1680-1691.

Abstract

In animals, microRNAs frequently form families with related sequences. The functional relevance of miRNA families and the relative contribution of family members to target repression have remained, however, largely unexplored. Here, we used the Caenorhabditis elegans miR-58 miRNA family, composed primarily of the four highly abundant members miR-58.1, miR-80, miR-81, and miR-82, as a model to investigate the redundancy of miRNA family members and their impact on target expression in an in vivo setting. We found that miR-58 family members repress largely overlapping sets of targets in a predominantly additive fashion. Progressive deletions of miR-58 family members lead to cumulative up-regulation of target protein and RNA levels. Phenotypic defects could only be observed in the family quadruple mutant, which also showed the strongest change in target protein levels. Interestingly, although the seed sequences of miR-80 and miR-58.1 differ in a single nucleotide, predicted canonical miR-80 targets were efficiently up-regulated in the mir-58.1 single mutant, indicating functional redundancy of distinct members of this miRNA family. At the aggregate level, target binding leads mainly to mRNA degradation, although we also observed some degree of translational inhibition, particularly in the single miR-58 family mutants. These results provide a framework for understanding how miRNA family members interact to regulate target mRNAs.

Abstract

In animals, microRNAs frequently form families with related sequences. The functional relevance of miRNA families and the relative contribution of family members to target repression have remained, however, largely unexplored. Here, we used the Caenorhabditis elegans miR-58 miRNA family, composed primarily of the four highly abundant members miR-58.1, miR-80, miR-81, and miR-82, as a model to investigate the redundancy of miRNA family members and their impact on target expression in an in vivo setting. We found that miR-58 family members repress largely overlapping sets of targets in a predominantly additive fashion. Progressive deletions of miR-58 family members lead to cumulative up-regulation of target protein and RNA levels. Phenotypic defects could only be observed in the family quadruple mutant, which also showed the strongest change in target protein levels. Interestingly, although the seed sequences of miR-80 and miR-58.1 differ in a single nucleotide, predicted canonical miR-80 targets were efficiently up-regulated in the mir-58.1 single mutant, indicating functional redundancy of distinct members of this miRNA family. At the aggregate level, target binding leads mainly to mRNA degradation, although we also observed some degree of translational inhibition, particularly in the single miR-58 family mutants. These results provide a framework for understanding how miRNA family members interact to regulate target mRNAs.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:31 July 2015
Deposited On:16 Dec 2015 16:39
Last Modified:14 Feb 2018 10:04
Publisher:Cold Spring Harbor Laboratory Press
ISSN:1088-9051
Funders:Swiss National Science Foundation Sinergia grant CRSII3_141942, University of Zurich Research Priority Program in Systems Biology, ETH Zurich, Swiss National Science Foundation (Marie-Heim Voegtlin, PMPDP3_122836), Seventh Framework Program of the European Union (contract no. 262067-PRIME-XS)
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/gr.183160.114
Official URL:http://www.genome.org/cgi/doi/10.1101/gr.183160.114

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