The miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 domain controls neonatal metabolic adaptation

Authors

  • Stéphane Labialle,

    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
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    • These authors contributed equally to this work
  • Virginie Marty,

    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
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    • These authors contributed equally to this work
  • Marie-Line Bortolin-Cavaillé,

    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
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  • Magali Hoareau-Osman,

    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
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  • Jean-Philippe Pradère,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
    2. Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Université Paul Sabatier, Toulouse, France
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  • Philippe Valet,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
    2. Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Université Paul Sabatier, Toulouse, France
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  • Pascal GP Martin,

    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
    3. INRA, UMR1331, TOXALIM (Research Centre in Food Toxicology), Toulouse, France
    4. Université de Toulouse, INP, UPS, TOXALIM, Toulouse, France
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  • Jérôme Cavaillé

    Corresponding author
    1. Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse, Toulouse, France
    2. CNRS, LBME, Toulouse, France
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Abstract

In mammals, birth entails complex metabolic adjustments essential for neonatal survival. Using a mouse knockout model, we identify crucial biological roles for the miR-379/miR-410 cluster within the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 locus, also named C14MC in humans, is the largest known placental mammal-specific miRNA cluster, whose 39 miRNA genes are expressed only from the maternal allele. We found that heterozygote pups with a maternal—but not paternal—deletion of the miRNA cluster display partially penetrant neonatal lethality with defects in the maintenance of energy homeostasis. This maladaptive metabolic response is caused, at least in part, by profound changes in the activation of the neonatal hepatic gene expression program, pointing to as yet unidentified regulatory pathways that govern this crucial metabolic transition in the newborn's liver. Not only does our study highlight the physiological importance of miRNA genes that recently evolved in placental mammal lineages but it also unveils additional layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on metabolic control at birth and have likely contributed to mammal evolution.

Synopsis

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Maternal expression of the imprinted miRNA cluster miR-379/miR-410 is central for metabolic adaptation in new-born mice, uncovering a physiological role for these miRNAs in regulating neonatal hepatic gene expression.

  • Genetic ablation of the mouse imprinted miR-379/miR-410 cluster (C14MC in human) leads to neonatal lethality with incomplete penetrance.
  • A subset of miR-379/miR-410-deficient pups have difficulties maintaining energy homeostasis in the safe range.
  • Lack of miR-379/miR-410 expression is associated with profound changes in the neonatal hepatic gene expression program at the transition from fetal to post-natal life.
  • This phenotype suggests a pivotal role for the miR-379/miR-410 cluster in neonatal survival very likely by controlling metabolic adaptation at birth.