Inducible and reversible inhibition of miRNA-mediated gene repression in vivo

  • Gaspare La Rocca
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Bryan King
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Bing Shui
    Department of Cancer Biology, Dana Farber Cancer Institute
  • Xiaoyi Li
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Minsi Zhang
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Kemal M Akat
    Laboratory of RNA Molecular Biology, The Rockefeller University
  • Paul Ogrodowski
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Chiara Mastroleo
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Kevin Chen
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Vincenzo Cavalieri
    Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
  • Yilun Ma
    Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program
  • Viviana Anelli
    Center of Integrative Biology, University of Trento
  • Doron Betel
    Hem/Oncology, Medicine and Institution for Computational Biomedicine, Weill Cornell Medical College
  • Joana Vidigal
    Laboratory of Biochemistry and Molecular Biology, National Cancer Institute
  • Thomas Tuschl
    Laboratory of RNA Molecular Biology, The Rockefeller University
  • Gunter Meister
    Regensburg Center for Biochemistry, University of Regensburg
  • Craig B Thompson
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
  • Tullia Lindsten
    Immunology Program, Memorial Sloan Kettering Cancer Center
  • Kevin Haigis
    Department of Cancer Biology, Dana Farber Cancer Institute
  • Andrea Ventura
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center

抄録

<jats:p>Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss-of-function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.</jats:p>

収録刊行物

  • eLife

    eLife 10 e70948-, 2021-08-31

    eLife Sciences Publications, Ltd

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