DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 46; pp. 18157 - 18162
• Main Authors: Dixit, Manjusha, Ansseau, Eugénie, Tassin, Alexandra, Winokur, Sara, Shi, Rongye, Qian, Hong, Sauvage, Sébastien, Mattéotti, Christel, van Acker, Anne M, Leo, Oberdan, Figlewicz, Denise, Barro, Marietta, Laoudj-Chenivesse, Dalila, Belayew, Alexandra, Coppée, Frédérique, Chen, Yi-Wen
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-11-2007; National Acad Sciences
• Subjects: Base Sequence; Biological Sciences; Chromosomes; DNA; Gene expression; Genes; Genetic vectors; Genomics; Homeodomain Proteins - genetics; Humans; Introns; Life Sciences; Messenger RNA; Muscular dystrophies; Muscular dystrophy; Muscular Dystrophy, Facioscapulohumeral - genetics; Mutation; Myoblasts; Neuromuscular diseases; Paired Box Transcription Factors - genetics; Promoter regions; Promoter Regions, Genetic; Proteins; Ribonucleic acid; RNA; Trans-Activators - genetics; Transcription factors; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0708659104

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5'-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3' in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.