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Publication Detail
β-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Banerji CRS, Knopp P, Moyle LA, Severini S, Orrell RW, Teschendorff AE, Zammit PS
  • Publication date:
    01/01/2015
  • Journal:
    Journal of the Royal Society Interface
  • Volume:
    12
  • Issue:
    102
  • Status:
    Published
  • Print ISSN:
    1742-5689
Abstract
© 2014 The Author(s) Published by the Royal Society. All rights reserved. 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 networkmethodology, 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 inmurinemyoblasts. Thus,we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.
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