1. Genetics and Genomics
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A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy

  1. Qing Feng
  2. Lauren Snider
  3. Sujatha Jagannathan
  4. Rabi Tawil
  5. Silvère M van der Maarel
  6. Stephen J Tapscott
  7. Robert K Bradley  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Rochester, United States
  3. Leiden University Medical Center, Netherlands
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Cite this article as: eLife 2015;4:e04996 doi: 10.7554/eLife.04996

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when mis-expressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis.

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Author details

  1. Qing Feng

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Lauren Snider

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sujatha Jagannathan

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Rabi Tawil

    Department of Neurology, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Silvère M van der Maarel

    Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  6. Stephen J Tapscott

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Robert K Bradley

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    rbradley@fhcrc.org
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Rachel Green, HHMI, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: October 1, 2014
  2. Accepted: January 7, 2015
  3. Accepted Manuscript published: January 7, 2015 (version 1)
  4. Accepted Manuscript updated: January 15, 2015 (version 2)
  5. Version of Record published: February 5, 2015 (version 3)

Copyright

© 2015, Feng 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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