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      Telomere Position Effect (TPE) Regulates DUX4 in Human Facioscapulohumeral Muscular Dystrophy (FSHD)

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          Abstract

          Telomeres may regulate human disease by at least two independent mechanisms. 1) Replicative senescence occurs once short telomeres generate DNA damage signals that produce a barrier to tumor progression. 2) Telomere Position Effect (TPE) can change gene expression at intermediate telomere lengths in cultured human cells. We here report a human disease, facioscapulohumeral muscular dystrophy (FSHD) where telomere length may well contribute to its pathogenesis. FSHD is age-related and genetically only 25-60 kb from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated >10-fold in FSHD myoblasts-myotubes with short versus long telomeres, and its expression is inversely proportional to telomere length. FSHD may represent a human disease in which TPE contributes to its age-related phenotype.

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          Author and article information

          Journal
          101186374
          31761
          Nat Struct Mol Biol
          Nat. Struct. Mol. Biol.
          Nature structural & molecular biology
          1545-9993
          1545-9985
          11 April 2013
          05 May 2013
          June 2013
          01 December 2013
          : 20
          : 6
          : 671-678
          Affiliations
          [1 ]Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
          [2 ]Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
          [3 ]Program in Genomics, Division of Genetics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115
          [4 ]Boston Biomedical Research Institute, Watertown, MA 02472
          [6 ]The Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, MD 21205
          [7 ]Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205
          [8 ]CEGMR, King Abulaziz University, Jeddah, Saudi Arabia
          Author notes
          Corresponding author: Woodring E. Wright, M.D., Ph.D. Department of Cell Biology UT Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, TX 75390-9039 Tel: 214-633-1996 Woodring.wright@ 123456utsouthwestern.edu
          [5]

          Current address: Wellstone Program, Department of Cell & Developmental Biology and Neurology, University of Massachusetts Medical School, Worcester, MA 01655

          Article
          NIHMS457969
          10.1038/nsmb.2571
          3711615
          23644600
          33d63ec5-761a-48d5-b65a-36b96ea57693

          Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

          History
          Funding
          Funded by: National Institute on Aging : NIA
          Award ID: R01 AG001228 || AG
          Categories
          Article

          Molecular biology
          aging,muscle,d4z4 repeats,chromosome 4q,telomere shortening
          Molecular biology
          aging, muscle, d4z4 repeats, chromosome 4q, telomere shortening

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