1. Chromosomes and Gene Expression
  2. Genetics and Genomics
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PUMILIO hyperactivity drives premature aging of Norad-deficient mice

  1. Florian Kopp
  2. Mahmoud M Elguindy
  3. Mehmet E Yalvac
  4. He Zhang
  5. Beibei Chen
  6. Frank A Gillett
  7. Sungyul Lee
  8. Sushama Sivakumar
  9. Hongtao Yu
  10. Yang Xie
  11. Prashant Mishra
  12. Zarife Sahenk
  13. Joshua T Mendell  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Nationwide Children's Hospital, United States
Research Article
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Cite this article as: eLife 2019;8:e42650 doi: 10.7554/eLife.42650

Abstract

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.

Article and author information

Author details

  1. Florian Kopp

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mahmoud M Elguindy

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9151-1751
  3. Mehmet E Yalvac

    Center for Gene Therapy, Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. He Zhang

    Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Beibei Chen

    Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Frank A Gillett

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sungyul Lee

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3207-1199
  8. Sushama Sivakumar

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7877-4821
  9. Hongtao Yu

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8861-049X
  10. Yang Xie

    Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Prashant Mishra

    Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Zarife Sahenk

    Center for Gene Therapy, Nationwide Children's Hospital, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Joshua T Mendell

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    joshua.mendell@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8479-2284

Funding

Howard Hughes Medical Institute

  • Hongtao Yu
  • Joshua T Mendell

National Institutes of Health (R35CA197311)

  • Joshua T Mendell

Cancer Prevention and Research Institute of Texas (RP160249)

  • Yang Xie
  • Joshua T Mendell

Welch Foundation (I-1961-20180324)

  • Joshua T Mendell

German National Academy of Sciences Leopoldina (LPDS 2014-12)

  • Florian Kopp

National Institutes of Health (P30CA142543)

  • Joshua T Mendell

National Institutes of Health (P50CA196516)

  • Joshua T Mendell

Cancer Prevention and Research Institute of Texas (RP150596)

  • Yang Xie
  • Joshua T Mendell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols of The University of Texas Southwestern Medical Center (Animal Protocol Number 2017-102001) and The Ohio State University, Nationwide Children's Hospital (Animal Protocol Number AR12-00014).

Reviewing Editor

  1. Chris P Ponting, University of Edinburgh, United Kingdom

Publication history

  1. Received: October 7, 2018
  2. Accepted: February 5, 2019
  3. Accepted Manuscript published: February 8, 2019 (version 1)
  4. Version of Record published: March 8, 2019 (version 2)

Copyright

© 2019, Kopp et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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