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论文题目: beta-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy
英文论文题目: beta-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy
第一作者: Banerji, CRS; Knopp, P; Moyle, LA; Severini, S; Orrell, RW; Teschendorff, AE; Zammit, PS
英文第一作者: Banerji, CRS; Knopp, P; Moyle, LA; Severini, S; Orrell, RW; Teschendorff, AE; Zammit, PS
联系作者: Banerji, CRS (reprint author), UCL, UCL Canc Inst, Paul OGorman Bldg, London WC1E 6BT, England.
英文联系作者: Banerji, CRS (reprint author), UCL, UCL Canc Inst, Paul OGorman Bldg, London WC1E 6BT, England.
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发表年度: 2015
卷: 12
期: 102
页码: -
摘要: 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.
英文摘要: 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.
刊物名称: JOURNAL OF THE ROYAL SOCIETY INTERFACE
英文刊物名称: JOURNAL OF THE ROYAL SOCIETY INTERFACE
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学科: Science & Technology - Other Topics
英文学科: Science & Technology - Other Topics
影响因子: 3.917
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论文类别: Article
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