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

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.

Article and author information

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.

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.

Metrics

  • 4,093
    views
  • 680
    downloads
  • 96
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2015)
A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy
eLife 4:e04996.
https://doi.org/10.7554/eLife.04996

Share this article

https://doi.org/10.7554/eLife.04996

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Omid Gholamalamdari, Tom van Schaik ... Andrew S Belmont
    Research Article

    Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here, we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Although gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.