Looking for a needle in a haystack: de novo phenotypic target identification reveals Hippo pathway-mediated miR-202 regulation of egg production

Author:

Janati-Idrissi Sarah1,de Abreu Mariana Roza1,Guyomar Cervin2ORCID,de Mello Fernanda1,Nguyen Thaovi1,Mechkouri Nazim3,Gay Stéphanie1,Montfort Jérôme1,Gonzalez Anne Alicia4,Abbasi Marzieh1,Bugeon Jérôme1,Thermes Violette1ORCID,Seitz Hervé3ORCID,Bobe Julien1ORCID

Affiliation:

1. INRAE, UR1037, LPGP , Rennes , France

2. Sigenae, GenPhySE, Université de Toulouse, INRAE, ENVT , Castanet Tolosan , France

3. Institut de Génétique Humaine, UMR 9002 CNRS and University of Montpellier , Montpellier , France

4. MGX-Montpellier GenomiX, University of Montpellier, CNRS, INSERM , Montpellier , France

Abstract

Abstract Understanding microRNA (miRNA) functions has been hampered by major difficulties in identifying their biological target(s). Currently, the main limitation is the lack of a suitable strategy to identify biologically relevant targets among a high number of putative targets. Here we provide a proof of concept of successful de novo (i.e. without prior knowledge of its identity) miRNA phenotypic target (i.e. target whose de-repression contributes to the phenotypic outcomes) identification from RNA-seq data. Using the medaka mir-202 knock-out (KO) model in which inactivation leads to a major organism-level reproductive phenotype, including reduced egg production, we introduced novel criteria including limited fold-change in KO and low interindividual variability in gene expression to reduce the list of 2853 putative targets to a short list of 5. We selected tead3b, a member of the evolutionarily-conserved Hippo pathway, known to regulate ovarian functions, due to its remarkably strong and evolutionarily conserved binding affinity for miR-202-5p. Deleting the miR-202-5p binding site in the 3′ UTR of tead3b, but not of other Hippo pathway members sav1 and vgll4b, triggered a reduced egg production phenotype. This is one of the few successful examples of de novo functional assignment of a miRNA phenotypic target in vivo in vertebrates.

Funder

Agence Nationale de la Recherche

Publisher

Oxford University Press (OUP)

Subject

Genetics

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