Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy

Guido Stadler, Fedik Rahimov, Oliver D. King, Jennifer C J Chen, Jerome D. Robin, Kathryn R. Wagner, Jerry W. Shay, Charles P. Emerson, Woodring E. Wright

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)671-678
Number of pages8
JournalNature Structural and Molecular Biology
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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