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

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...

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Bibliographic Details
Published in:	Nucleic acids research Vol. 52; no. 2; pp. 738 - 754
Main Authors:	Janati-Idrissi, Sarah, de Abreu, Mariana Roza, Guyomar, Cervin, de Mello, Fernanda, Nguyen, Thaovi, Mechkouri, Nazim, Gay, Stéphanie, Montfort, Jérôme, Gonzalez, Anne Alicia, Abbasi, Marzieh, Bugeon, Jérôme, Thermes, Violette, Seitz, Hervé, Bobe, Julien
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 25-01-2024
Subjects:	Genomics Life Sciences
Online Access:	Get full text
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Summary:	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. Graphical Abstract Graphical Abstract
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The first two authors should be regarded as Joint First Authors.
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkad1154