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Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy

Nature Structural & Molecular Biology volume 20, pages 671678 (2013) | Download Citation


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Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25–60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.

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  • 19 May 2013

    In the version of the Online Methods originally posted online, materials received from a collaborator were not appropriately acknowledged. The fifth sentence in the first paragraph of Online Methods has been replaced with two new sentences reflecting the material transfer agreement as of 19 May 2013.


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All authors were supported by the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (US National Institutes of Health 5U54HD060848). Additional support was provided by the Austrian Science Fund and the American Federation for Aging Research (G.S.), AG01228 from the US National Institute of Aging (W.E.W.), the Muscular Dystrophy Association (F.R.) and P50 CA70907 from the US National Institutes of Health (J.W.S.). We thank D. Leung (Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA) for obtaining phenotypes and muscle biopsies along with K.R.W., G. Bibat (Kennedy Krieger Institute, Johns Hopkins School of Medicine Baltimore, Maryland, USA) and D. Perez (FSH Society, Lexington, Massachusetts, USA) for subject recruitment and outreach, N. Liu for technical assistance, T. Jones for discussions and S. van der Maarel (Leiden University Medical Center, Leiden, Netherlands) and A. Belayew (University of Mons, Mons, Belgium) for reporter constructs.

Author information

Author notes

    • Oliver D King
    • , Jennifer C J Chen
    •  & Charles P Emerson Jr

    Present address: Wellstone Program, Department of Cell and Developmental Biology and Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.


  1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Guido Stadler
    • , Jerome D Robin
    • , Jerry W Shay
    •  & Woodring E Wright
  2. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, Watertown, Massachusetts, USA.

    • Guido Stadler
    • , Fedik Rahimov
    • , Oliver D King
    • , Jennifer C J Chen
    • , Jerome D Robin
    • , Kathryn R Wagner
    • , Charles P Emerson Jr
    •  & Woodring E Wright
  3. Program in Genomics, Division of Genetics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Fedik Rahimov
  4. Boston Biomedical Research Institute, Watertown, Massachusetts, USA.

    • Oliver D King
    • , Jennifer C J Chen
    •  & Charles P Emerson Jr
  5. Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland, USA.

    • Kathryn R Wagner
  6. Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Kathryn R Wagner
  7. Center of Excellence in Genomic Medicine Research, King Abulaziz University, Jeddah, Saudi Arabia.

    • Jerry W Shay


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G.S. helped design and executed most of the experiments and contributed to the writing of the manuscript, W.E.W. designed the experiments and wrote the manuscript, K.R.W. obtained phenotypes and muscle biopsies, J.C.J.C. established the primary muscle cultures, F.R. performed the microfluidics expression analysis, O.D.K. analyzed the probability of expression per cell and other statistical measures, J.D.R. helped generate reversibly immortalized muscle cultures with different telomere lengths, C.P.E. coordinated the efforts of all members of the Wellstone consortium, and all authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Woodring E Wright.

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