title: DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.
abstract: 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.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Manjusha
authors.initials: M
authors.lastname: Dixit
authors.forename: Eugénie
authors.initials: E
authors.lastname: Ansseau
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tassin
authors.forename: Sara
authors.initials: S
authors.lastname: Winokur
authors.forename: Rongye
authors.initials: R
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sauvage
authors.forename: Christel
authors.initials: C
authors.lastname: Mattéotti
authors.forename: Anne M
authors.initials: AM
authors.lastname: van Acker
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
authors.forename: Denise
authors.initials: D
authors.lastname: Figlewicz
authors.forename: Marietta
authors.initials: M
authors.lastname: Barro
authors.forename: Dalila
authors.initials: D
authors.lastname: Laoudj-Chenivesse
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
authors.forename: Frédérique
authors.initials: F
authors.lastname: Coppée
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
mesh_terms: D001483:Base Sequence; D004247:DNA; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; C101485:homeobox protein PITX1; D004247:DNA