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B-Catenin Is Central to DUX4-Driven Network Rewiring in Facioscapulohumeral Rsif.Royalsocietypublishing.Org Muscular Dystrophy

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B-Catenin Is Central to DUX4-Driven Network Rewiring in Facioscapulohumeral Rsif.Royalsocietypublishing.Org Muscular Dystrophy Downloaded from http://rsif.royalsocietypublishing.org/ on November 26, 2014 b-catenin is central to DUX4-driven network rewiring in facioscapulohumeral rsif.royalsocietypublishing.org muscular dystrophy Christopher R. S. Banerji1,2,3,4,†, Paul Knopp4,†, Louise A. Moyle4, Research Simone Severini2, Richard W. Orrell5, Andrew E. Teschendorff1,6 4 Cite this article: Banerji CRS, Knopp P, Moyle and Peter S. Zammit LA, Severini S, Orrell RW, Teschendorff AE, 1Statistical Cancer Genomics, Paul O’Gorman Building, UCL Cancer Institute, Zammit PS. 2015 b-catenin is central to 2Department of Computer Science, and 3Centre of Mathematics and Physics in the Life Sciences and DUX4-driven network rewiring in Experimental Biology, University College London, London WC1E 6BT, UK 4Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, facioscapulohumeral muscular dystrophy. London SE1 1UL, UK J. R. Soc. Interface 12: 20140797. 5Department of Clinical Neuroscience, Institute of Neurology, University College London, Rowland Hill St., http://dx.doi.org/10.1098/rsif.2014.0797 London NW3 2PF, UK 6CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People’s Republic of China Received: 21 July 2014 Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is Accepted: 27 October 2014 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 patho- physiology, but an integrated molecular model is currently lacking. We Subject Areas: developed a novel differential network methodology, Interactome Sparsification bioinformatics, systems biology, biochemistry 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 Keywords: FSHD muscle biopsies, then removed secondary rewiring using non-FSHD facioscapulohumeral muscular dystrophy, datasets, to construct a unified network of rewired interactions. Our analysis meta-analysis, b-catenin, differential identified b-catenin as the main coordinator of FSHD-associated protein inter- networks, canonical Wnt signalling, DUX4 action signalling, with pathways including canonical Wnt, HIF1-a and TNF-a clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myo- blasts. This revealed that DUX4 significantly modified expression of the genes Authors for correspondence: in our FSHD network. Furthermore, we experimentally confirmed that Wnt/ Christopher R. S. Banerji b-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide e-mail: [email protected] the first unified molecular map of FSHD signalling, capable of uncovering Peter S. Zammit pathomechanisms and guiding therapeutic development. e-mail: [email protected] 1. Introduction Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inheritable disease of skeletal muscle, yet, due to the relative longevity of patients, it is the most prevalent muscular dystrophy (approx. 12/100 000 [1,2]). Despite such prevalence, no curative therapy exists. Clinically, FSHD is characterized by asymmetric, skeletal muscle atrophy affecting specific muscle groups, often associated with features including retinal vasculature † These authors contributed equally to this abnormalities and sensorineural hearing loss [1,3–5]. Approximately 95% of work. cases (FSHD1; OMIM158900) are associated with deletion of a number of 3.3 kb D4Z4 macrosatellite repeats on chromosome 4q35. Healthy individuals Electronic supplementary material is available typically have between 11 and 100 such repeats, whereas FSHD1 patients at http://dx.doi.org/10.1098/rsif.2014.0797 or have 1–10. Importantly, complete loss of D4Z4 units is not associated with FSHD. Each D4Z4 repeat contains an open reading frame for a transcription via http://rsif.royalsocietypublishing.org. factor, double homeobox 4 (DUX4) [6,7]. Reduced D4Z4 repeat number leads & 2014 The Author(s) Published by the Royal Society. All rights reserved. Downloaded from http://rsif.royalsocietypublishing.org/ on November 26, 2014 to hypomethylation, which on a permissive genetic back- DUX4 expression in human myoblasts perturbs a large pro- 2 ground supplying a polyadenylation signal, stabilizes portion of genes which are differentially expressed in FSHD rsif.royalsocietypublishing.org DUX4 transcripts from the last D4Z4 repeat. In the remain- [18]. Our analysis further demonstrates in a meta-analysis set- ing 5% of cases (FSHD2; OMIM158901), D4Z4 repeats are ting that signalling network rewiring in FSHD, independent not contracted, but become hypomethylated, likely through of atrophy, ageing and inflammation, can also be explained mutations in chromatin-modifying genes such as SMCHD1 by DUX4, lending more support to the hypothesis that [8]. Again on the permissive genetic background with a poly- DUX4 expression drives pathology. adenylation signal, this leads to DUX4 transcription from the To determine whether DUX4 expression results in b-catenin last D4Z4 repeat. Thus, aberrant DUX4 expression underlies signalling, we assayed readouts of the Wnt pathway and found FSHD pathogenesis in both FSHD1 and FSHD2 [9]. How significant DUX4-mediated activation of b-catenin signalling in DUX4 perturbs pathway interactions to produce the complex mouse myoblasts. Thus, we provide the first integrated FSHD FSHD phenotype is unclear, with many genes and pathways network, capable of explaining DUX4-driven pathomechanisms J. R. Soc. Interface implicated in FSHD. Indeed, the FSH Society FSHD Inter- and informing development of therapeutics. national Research Consortium has annually set uncovering FSHD molecular networks as a top research priority. Complex diseases are frequently examined by gene 2. Results expression profiling using an arrayed platform of cDNA probes 12 (microarray) and many datasets are published each year. These 2.1. Meta-analysis of facioscapulohumeral muscular : 20140797 describe healthy and diseased biological processes, including dystrophy datasets using InSpiRe FSHD and other muscular dystrophies and myopathies. How- InSpiRe is a differential network methodology we designed to ever, their use is often limited to selecting genes for further extract a subset of the human protein interaction network examination based on differential expression, evidence from containing proteins and interactions that are altered between the literature or intuition. Systems biology and network concepts, two phenotypes described by expression data. The three steps particularly the conceptual framework of differential networks of InSpiRe are summarized in figure 1, and explained in detail and network rewiring, allow higher order, unbiased analysis of in Material and methods. such data [10,11]. These approaches involve integration of Four human FSHD datasets were obtained from the GEO molecular profiles (especially gene or protein expression) with Database. GSE3307 [17,19] consisted of gene expression data network models of protein interactions [12,13], to identify from 14 skeletal muscle (nine biceps, five deltoid) biopsies either hotspots of differential expression, or a change in local from FSHD patients, and 14 skeletal muscle biopsies from interaction patterns-network rewiring. Although many healthy, matched control individuals. GSE10760 [5] contains differential network algorithms exist [13,14], each has limitations. gene expression data from vastus lateralis biopsies from 19 Here, we developed a novel differential network algor- FSHD patients and 30 control individuals. Both GSE3307 and ithm based on information theoretic principles that we call GSE10760 were profiled on the Affymetrix Human Genome Interactome Sparsification and Rewiring (InSpiRe). InSpiRe U133A Array platform. GSE26145 [20] and GSE26061 [21] are detects shifts in active pathway regimes, identifying proteins exon array studies using the Affymetrix Human Exon 1.0 ST from the human interactome displaying a wide class of rewir- Array each profiling three myoblast and three myotube samples ing events between two phenotypes. This protein set is from either quadriceps, rhomboid or deltoid muscles of three constructed into a sub-network, which is sparsified to FSHD patients and three control individuals. As only isolated describe pathways altered between phenotypes. cells were arrayed in GSE26145 [20] and GSE26061 [21], non- Here, we performed a meta-analysis with InSpiRe on multi- muscle gene expression was assumed to be low/negligible. ple FSHD and healthy human control datasets to identify These studies were employed in our meta-analysis to refine network rewiring. Rewiring associated with ageing, disuse the larger datasets of primary muscle biopsies of GSE3307 atrophy, inflammation and muscle wasting was then subtracted [17,19] and GSE10760 [5]. All datasets were pre-processed and to construct a unified FSHD-specific disease network. Our FSHD normalized as described in Material and methods. network is significantly more connected than expected by chance Approximately 3500 genes were implicated
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