Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation
Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation
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DOI：
10.1093/hmg/ddg327
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发表时间：
2003-11-15
影响因子：
3.5
通讯作者：
Flanigan, KM
中科院分区：
文献类型：
--
作者：
Winokur, ST;Chen, YW;Flanigan, KM
神经肌肉疾病面肩肱型肌营养不良症（FSHD）是由染色体4q上亚端粒重复序列D4Z4的完整缺失引起的。影响基因表达的染色质结构的破坏被认为是病理生理学的基础。这里提出的成熟肌肉组织的全局基因表达谱提供了第一个洞察肌源性分化中的FSHD特异性缺陷。将寡核苷酸微阵列产生的FSHD表达谱与正常肌肉以及其他类型的肌营养不良症（DMD，aSGD）的FSHD表达谱进行比较，以确定FSHD特异性变化。此外，来自FSHD个体的匹配活检（受影响和未受影响的肌肉）用于监测疾病进展期间的表达变化，以及减少由个体变异性引起的非特异性变化。在以FSHD特异性和高度显著的方式改变的基因中，许多基因参与肌源性分化，并表明正常分化程序中的部分阻断。事实上，FSHD中受影响的许多转录物代表转录因子MyoD的直接靶点。额外的错误表达基因证实了缓冲氧化应激的能力减弱，如FSHD成肌细胞所示。增殖期成肌细胞对活性氧的这种增强的脆弱性也是疾病特异性的，进一步暗示了FSHD肌肉卫星细胞的缺陷。重要的是，没有发现定位于FSHD区域4q35的基因在FSHD肌肉中表现出显著改变的表达模式。这一发现得到了FSHD肌肉表达分析的证实，使用自定义的cDNA微阵列包含51个基因和EST从4q35区域。因此，FSHD肌生成和氧化能力的中断可能不是如先前所建议的那样由位置效应机制引起的，而是由对基因调控的全局效应引起的。不正确的核定位的4qter作为一个替代模型FSHD基因调控和发病机制进行了讨论。
The neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD) results from integral deletions of the subtelomeric repeat D4Z4 on chromosome 4q. A disruption of chromatin structure affecting gene expression is thought to underlie the pathophysiology. The global gene expression profiling of mature muscle tissue presented here provides the first insight into an FSHD-specific defect in myogenic differentiation. FSHD expression profiles generated by oligonucleotide microarrays were compared with those from normal muscle as well as other types of muscular dystrophies (DMD, aSGD) in order to determine FSHD-specific changes. In addition, matched biopsies (affected and unaffected muscle) from individuals with FSHD served to monitor expression changes during the progression of the disease as well as to diminish non-specific changes resulting from individual variability. Among genes altered in an FSHD-specific and highly significant manner, many are involved in myogenic differentiation and suggest a partial block in the normal differentiation program. Indeed, many of the transcripts affected in FSHD represent direct targets of the transcription factor MyoD. Additional mis-expressed genes confirm a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species is also disease-specific, further implicating a defect in FSHD muscle satellite cells. Importantly, none of the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly altered pattern of expression in FSHD muscle. This finding was corroborated by expression analysis of FSHD muscle using a custom cDNA microarray containing 51 genes and ESTs from the 4q35 region. Disruptions in FSHD myogenesis and oxidative capacity may therefore not arise from a position effect mechanism as has been previously suggested, but rather from a global effect on gene regulation. Improper nuclear localization of 4qter is discussed as an alternative model for FSHD gene regulation and pathogenesis.