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

TY - JOUR

T1 - beta-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy

AU - Banerji, Christopher R. S.

AU - Knopp, Paul

AU - Moyle, Louise A.

AU - Severini, Simone

AU - Orrell, Richard W.

AU - Teschendorff, Andrew E.

AU - Zammit, Peter S.

PY - 2015/1/6

Y1 - 2015/1/6

N2 - 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.

AB - 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.

KW - facioscapulohumeral muscular dystrophy

KW - meta-analysis

KW - beta-catenin

KW - differential networks

KW - canonical Wnt signalling

KW - DUX4

KW - ACTIVATED PROTEIN-KINASE

KW - HUMAN SKELETAL-MUSCLE

KW - GENE-EXPRESSION

KW - CELL-DEATH

KW - MYOGENIC PROGRESSION

KW - SIGNAL-TRANSDUCTION

KW - SATELLITE CELLS

KW - CANDIDATE GENE

KW - HEARING-LOSS

KW - FSHD

U2 - 10.1098/rsif.2014.0797

DO - 10.1098/rsif.2014.0797

M3 - Article

SN - 1742-5689

VL - 12

JO - Journal Of The Royal Society Interface

JF - Journal Of The Royal Society Interface

IS - 102

M1 - 20140797

ER -