beta-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy

Christopher R. S. Banerji*, Paul Knopp, Louise A. Moyle, Simone Severini, Richard W. Orrell, Andrew E. Teschendorff, Peter S. Zammit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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 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.

Original languageEnglish
Article number20140797
Number of pages15
JournalJournal Of The Royal Society Interface
Volume12
Issue number102
DOIs
Publication statusPublished - 6 Jan 2015

Keywords

  • facioscapulohumeral muscular dystrophy
  • meta-analysis
  • beta-catenin
  • differential networks
  • canonical Wnt signalling
  • DUX4
  • ACTIVATED PROTEIN-KINASE
  • HUMAN SKELETAL-MUSCLE
  • GENE-EXPRESSION
  • CELL-DEATH
  • MYOGENIC PROGRESSION
  • SIGNAL-TRANSDUCTION
  • SATELLITE CELLS
  • CANDIDATE GENE
  • HEARING-LOSS
  • FSHD

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