title: DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.
abstract: OBJECTIVE
  Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4-encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4.
  
  
  METHODS
  We delivered DUX4 to zebrafish and mouse muscle by transposon-mediated transgenesis and adeno-associated viral vectors, respectively.
  
  
  RESULTS
  Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4-induced damage.
  
  
  CONCLUSIONS
  Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis.
authors: Molecular, Cellular, and Developmental Biology Graduate Program, Ohio State University, Columbus, USA.
authors: Lindsay M
authors: LM
authors: Wallace
authors: Sara E
authors: SE
authors: Garwick
authors: Wenyan
authors: W
authors: Mei
authors: Alexandra
authors: A
authors: Belayew
authors: Frederique
authors: F
authors: Coppee
authors: Katherine J
authors: KJ
authors: Ladner
authors: Denis
authors: D
authors: Guttridge
authors: Jing
authors: J
authors: Yang
authors: Scott Q
authors: SQ
authors: Harper
mesh_terms: D000818:Animals; D005260:Female; D018014:Gene Transfer Techniques; D018737:Hand Strength / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015027:Zebrafish
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53