title: β-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy.
abstract: 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 β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α 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/β-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.
authors.forename: Christopher R S
authors.initials: CR
authors.lastname: Banerji
authors.forename: Paul
authors.initials: P
authors.lastname: Knopp
authors.forename: Louise A
authors.initials: LA
authors.lastname: Moyle
authors.forename: Simone
authors.initials: S
authors.lastname: Severini
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
mesh_terms: D000465:Algorithms; D000818:Animals; D001706:Biopsy; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D009132:Muscles / Q000473:pathology / Q000502:physiology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; C532958:Dux4 protein, mouse; C497443:Hif1a protein, mouse; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051176:beta Catenin; D048670:MAP Kinase Kinase 4