The FSHD atrophic myotube phenotype is caused by DUX4 expression.
The FSHD atrophic myotube phenotype is caused by DUX4 expression.
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DOI：
10.1371/journal.pone.0026820
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Belayew A
中科院分区：
文献类型：
--
作者：
Vanderplanck C;Ansseau E;Charron S;Stricwant N;Tassin A;Laoudj-Chenivesse D;Wilton SD;Coppée F;Belayew A
面肩肩周肌营养不良(FSHD)与D4Z4重复序列中4q35的缺失有关，我们在其中发现了双同源盒4(DUX4)基因。我们发现稳定的DUX4 mRNAs只来自最远端的D4Z4单位，并且意外地延伸到提供内含子和多聚腺苷化信号的侧翼PLAM区域。DUX4编码一种转录因子，在FSHD中表达，但不控制原代成肌细胞或肌肉活检。DUX4蛋白启动了一个大的转录失调级联反应，导致肌肉萎缩和氧化应激，这是FSHD的关键特征。我们现在发现，将DUX4表达载体导入成肌细胞可导致萎缩的肌管形成，这与肌肉萎缩典型的E3泛素连接酶(MuRF1和Atrogin1/MAFbx)的诱导有关。DUX4可诱导FSHD下游靶基因的表达，如Mu-Crystal allin和TP53。我们开发了针对DUX4 mRNA的特异性siRNA和反义寡核苷酸(AO)。在原代培养的FSHD成肌细胞中加入这些反义药物可抑制DUX4蛋白的表达，并影响上述标志物的表达。这些结果为开发针对DUX4表达的FSHD治疗方法提供了概念证明。
Facioscapulohumeral muscular dystrophy (FSHD) is linked to deletions in 4q35 within the D4Z4 repeat array in which we identified the double homeobox 4 (DUX4) gene. We found stable DUX4 mRNAs only derived from the most distal D4Z4 unit and unexpectedly extended to the flanking pLAM region that provided an intron and a polyadenylation signal. DUX4 encodes a transcription factor expressed in FSHD but not control primary myoblasts or muscle biopsies. The DUX4 protein initiates a large transcription deregulation cascade leading to muscle atrophy and oxidative stress, which are FSHD key features. We now show that transfection of myoblasts with a DUX4 expression vector leads to atrophic myotube formation associated with the induction of E3 ubiquitin ligases (MuRF1 and Atrogin1/MAFbx) typical of muscle atrophy. DUX4 induces expression of downstream targets deregulated in FSHD such as mu-crystallin and TP53. We developed specific siRNAs and antisense oligonucleotides (AOs) targeting the DUX4 mRNA. Addition of these antisense agents to primary FSHD myoblast cultures suppressed DUX4 protein expression and affected expression of the above-mentioned markers. These results constitute a proof of concept for the development of therapeutic approaches for FSHD targeting DUX4 expression.
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影响因子：
2.9
作者：
Braasch, DA;Jensen, S;Corey, DR
通讯作者：
Corey, DR
影响因子：
64.8
作者：
Gabellini, D;D'Antona, G;Tupler, R
通讯作者：
Tupler, R
DOI：
10.1073/pnas.89.19.9292
发表时间：
1992-10-01
影响因子：
11.1
作者：
KIM, RY;GASSER, R;WISTOW, GJ
通讯作者：
WISTOW, GJ
影响因子：
3.5
作者：
Mann, CJ;Honeyman, K;Wilton, SD
通讯作者：
Wilton, SD
影响因子：
9.9
作者：
de Greef, J. C.;Lemmers, R. J. L. F.;Tawil, R.
通讯作者：
Tawil, R.