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Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy

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Abstract

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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Figure 1: Telomere position effect and FSHD.
Figure 2: DUX4, FRG2 and FRG1 expression in cells with short and long telomeres.
Figure 3: Linear correlation of DUX4 expression and telomere length.
Figure 4: Trans-acting factors change with differentiation but not with telomere length.
Figure 5: Functional DUX4-fl is upregulated in cells with short telomeres.
Figure 6: Estimating the fraction of cells expressing DUX4 and counts per cell that do express DUX4.

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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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Acknowledgements

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.

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Contributions

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.

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Correspondence to Woodring E Wright.

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The authors declare no competing financial interests.

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Stadler, G., Rahimov, F., King, O. et al. Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Nat Struct Mol Biol 20, 671–678 (2013). https://doi.org/10.1038/nsmb.2571

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