DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.
DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.
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DOI：
10.1016/j.devcel.2011.11.013
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发表时间：
2012-01-17
影响因子：
11.8
通讯作者：
Tapscott, Stephen J.
中科院分区：
文献类型：
--
作者：
Geng, Linda N.;Yao, Zizhen;Snider, Lauren;Fong, Abraham P.;Cech, Jennifer N.;Young, Janet M.;van der Maarel, Silvere M.;Ruzzo, Walter L.;Gentleman, Robert C.;Tawil, Rabi;Tapscott, Stephen J.
面肩肱营养不良（FSHD）是最常见的遗传性肌营养不良症之一。致病基因仍有争议，病理生理机制不明。在这里，我们确定了与生殖系和早期干细胞发育相关的基因作为DUX4转录因子的靶点，DUX4是FSHD的主要候选基因。DUX4调控的基因在FSHD肌肉中可靠地检测到，但在对照中未检测到，这为DUX4的错误表达是FSHD的致病因素的模型提供了直接支持。此外，我们表明DUX4结合并激活来自一类MaLR内源性灵长类逆转录转座子的LTR元件，并抑制对病毒感染的先天免疫应答，至少部分通过激活DEFB 103，一种可以抑制肌肉分化的人类防御素。这些发现提示了FSHD病理学的特定机制，并确定了用于疾病诊断和进展的候选生物标志物。
Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.
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