DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation
DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation
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DOI：
10.1016/j.expneurol.2008.07.022
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发表时间：
2008-11-01
影响因子：
5.3
通讯作者：
Kyba, Michael
中科院分区：
文献类型：
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作者：
Bosnakovski, Darko;Lamb, Sarah;Kyba, Michael
面肩肱型肌营养不良症（FSHD）是一种常染色体显性遗传性神经肌肉疾病。它映射到 4q35 处的 D4Z4 重复序列，并与重复收缩相关，从而抑制局部基因的转录。这些基因中的哪一个（如果有的话）对肌肉具有致病性，并且通过什么分子机制尚不清楚。本研究调查了一个候选基因 DUX4c 的功能，该基因由位于 D4Z4 重复序列附近 42 kb 处的截短反向 D4Z4 元件编码。我们使用功能获得方法测试了 DUX4c 的毒性和对 C2C12 成肌细胞分化的影响。表达 DUX4c 的成肌细胞形态正常，但肌源性调节因子（包括 MyoD 和 Myf5）的表达减少。与此一致的是，表达 DUX4c 的成肌细胞无法分化为肌管。此外，Myf.5 或 MyoD 的过度表达可挽救成肌细胞分化，表明这些调节因子表达的减少是 DUX4c 诱导的抑制分化的相关生理变化。出去。结果表明，DUX4c 的上调会对肌肉稳态和再生产生有害影响，并表明 DUX4c 在 FSHD 病理学中可能发挥作用。 (C) 2008 Elsevier Inc. 保留所有权利。
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease. It maps to the D4Z4 repeat array at 4q35, and correlates with a repeat contraction which derepresses transcription of local genes. Which, if any, of these genes is pathogenic to Muscle, and through what molecular mechanism is Unknown. The Present Study investigates the function of one candidate gene, DUX4c, encoded by a truncated inverted D4Z4 element located 42 kb proximal to the D4Z4 repeats. Using a gain of function approach we tested DUX4c for toxicity and effects on differentiation in C2C12 myoblasts. DUX4c-expressing myoblasts appear morphologically normal but have reduced expression of myogenic regulators, including MyoD and Myf5. Consistent with this, DUX4c-expressing myoblasts are unable to differentiate into myotubes. Furthermore, overexpression of Myf.5 or MyoD rescued myoblast differentiation, Suggesting that reductions in expression of these regulators are the relevant DUX4c-induced physiological changes that inhibit differentiation. Out. results Suggest that upregulation of DUX4c can have a deleterious effect on muscle homeostasis and regeneration, and point to a possible role for DUX4c in the pathology of FSHD. (C) 2008 Elsevier Inc. All rights reserved.