title: Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family in C. elegans.
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.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Molecular Life Sciences PhD Program, Swiss Federal Institute of Technology and University of Zurich, 8057 Zurich, Switzerland;
authors.forename: Deni
authors.initials: D
authors.lastname: Subasic
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland; Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA;
authors.forename: Anneke
authors.initials: A
authors.lastname: Brümmer
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Graduate Program in Areas of Basic and Applied Biology (GABBA), University of Porto, 4099-002 Porto, Portugal;
authors.forename: Sérgio Morgado
authors.initials: SM
authors.lastname: Pinto
authors.affiliation: Institute of Pharmaceutical Chemistry, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Jochen
authors.initials: J
authors.lastname: Imig
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Molecular Life Sciences PhD Program, Swiss Federal Institute of Technology and University of Zurich, 8057 Zurich, Switzerland;
authors.forename: Martin
authors.initials: M
authors.lastname: Keller
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland;
authors.forename: Marko
authors.initials: M
authors.lastname: Jovanovic
authors.affiliation: Institute of Pharmaceutical Chemistry, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Helen Louise
authors.initials: HL
authors.lastname: Lightfoot
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Sara
authors.initials: S
authors.lastname: Nasso
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Sandra
authors.initials: S
authors.lastname: Goetze
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland;
authors.forename: Erich
authors.initials: E
authors.lastname: Brunner
authors.affiliation: Institute of Pharmaceutical Chemistry, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hall
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland; Faculty of Science, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland;
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D063185:Epigenetic Repression; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D029742:Caenorhabditis elegans Proteins; C000599211:MIRN58 microRNA, C elegans; C587166:MIRN80 microRNA, C elegans; D035683:MicroRNAs; D012333:RNA, Messenger