DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.
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.
Dixit
Manjusha
M
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
Ansseau
Eugénie
E
Tassin
Alexandra
A
Winokur
Sara
S
Shi
Rongye
R
Qian
Hong
H
Sauvage
Sébastien
S
Mattéotti
Christel
C
van Acker
Anne M
AM
Leo
Oberdan
O
Figlewicz
Denise
D
Barro
Marietta
M
Laoudj-Chenivesse
Dalila
D
Belayew
Alexandra
A
Coppée
Frédérique
F
Chen
Yi-Wen
YW
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
C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; C101485:homeobox protein PITX1; D004247:DNA