β-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy
β-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy
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DOI：
10.1098/rsif.2014.0797
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发表时间：
2015-01-06
影响因子：
3.9
通讯作者：
Zammit, Peter S.
中科院分区：
文献类型：
--
作者：
Banerji, Christopher R. S.;Knopp, Paul;Zammit, Peter S.
面肩肱型肌营养不良症（FSHD）是一种无法治愈的疾病，其特征是骨骼肌无力和萎缩。从遗传学上来说，FSHD 的特点是 4 号染色体上 D4Z4 重复单元的收缩或低甲基化，这会导致最后一个重复的转录因子 DUX4 的异常表达。许多基因与 FSHD 病理生理学有关，但目前缺乏综合的分子模型。我们开发了一种新颖的差分网络方法，Interactome Sparsification and Rewiring (InSpiRe)，它通过将基因表达数据与已知的蛋白质相互作用相结合来检测表型之间的网络重新连接。使用 InSpiRe，我们对 FSHD 肌肉活检的多个微阵列数据集进行了荟萃分析，然后使用非 FSHD 数据集删除了二次重新连线，以构建重新连线相互作用的统一网络。我们的分析确定 β-连环蛋白是 FSHD 相关蛋白相互作用信号传导的主要协调者，包括典型 Wnt、HIF1-α 和 TNF-α 在内的通路明显受到干扰。为了检测 DUX4 直接引起的转录变化，使用微阵列对小鼠成肌细胞进行基因表达谱分析。这表明 DUX4 显着改变了 FSHD 网络中基因的表达。此外，我们通过实验证实 Wnt/β-catenin 信号传导受到小鼠成肌细胞中 DUX4 的影响。因此，我们提供了第一个统一的 FSHD 信号分子图谱，能够揭示病理机制并指导治疗开发。
Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified beta-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-alpha and TNF-alpha clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/beta-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.