DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1
DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1
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DOI：
10.1073/pnas.0708659104
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发表时间：
2007-11-13
影响因子：
11.1
通讯作者：
Chen, Yi-Wen
中科院分区：
文献类型：
--
作者：
Dixit, Manjusha;Ansseau, Eugenie;Chen, Yi-Wen
面肩肱型肌营养不良症（FSHD）是一种常染色体显性遗传疾病，与染色体4 q端粒下区域D4 Z4重复序列的收缩有关。通过比较来自FSHD患者肌肉活检的全基因组基因表达数据与其他11种神经肌肉疾病的基因组基因表达数据，发现FSHD患者的配对样同源结构域转录因子1（PITX 1）特异性上调。此外，我们发现，双同源框4基因（DUX 4）的地图内的D4 Z4重复单位上调患者成肌细胞在mRNA和蛋白质水平。我们进一步表明DUX 4蛋白可以激活与Pitx 1启动子融合的荧光素酶报告基因以及转染的C2 C12细胞中的内源Pitx 1基因的瞬时表达。在EMSA中，DUX 4特异性地与Pitx 1启动子中的30-bp序列5 '-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3'相互作用。TAAT核心的突变影响C2 C12细胞中Pitx 1-LUC的活化和体外DUX 4结合。我们的结果表明，FSHD肌肉中DUX 4和PITX 1的上调可能在该疾病的分子机制中发挥关键作用。
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.