<i>DUX4</i>, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

Wallace, Lindsay; Garwick, Sara E.; Mei, Wenyan; Belayew, Alexandra; Coppée, Frédérique; Ladner, Katherine J.; Guttridge, Denis C.; Yang, Jing; Harper, Scott Q.

doi:10.1002/ana.22275

Cited by 222 publications

(295 citation statements)

References 60 publications

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“…Our analysis confirms previous findings on processes and signalling pathways perturbed in FSHD, such as myogenesis, oxidative stress sensitivity, actin cytoskeletal signalling, Wnt/ b-catenin signalling and p53-mediated apoptosis [4,[15][16][17]. Importantly, we also describe novel FSHD molecular mechanisms.…”

Section: Introductionsupporting

confidence: 90%

“…TP53 [16], JUNB [20,17], HIF1A [20], WNT3 [4], LMO3 [20], ANXA4 [5] and HSPB1 [22]. Gene Set Enrichment Analysis (GSEA) [23] on the intersection also implicated many FSHD associated processes, such as myogenesis [17] and regulation of the actin cytoskeleton [15], and pathways, including, p53 [16], Wnt [4], and VEGF [5] To identify genes implicated as rewiring specifically in FSHD, we also ran InSpiRe on two datasets each describing skeletal muscle gene expression during ageing (GSE5086 [24] and GSE9676 [25]), disuse atrophy (GSE5110 [26] and GSE8872 [27]) and other muscle diseases involving inflammation and wasting (GSE3307 [19], where juvenile dermatomyositis and limb-girdle muscular dystrophy type 2A datasets were independently analysed). Genes rewiring in these non-FSHD datasets were considered as secondary rewiring.…”

Section: Meta-analysis Of Facioscapulohumeral Muscular Dystrophy Datamentioning

confidence: 99%

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

Banerji

Knopp

Moyle

et al. 2015

J. R. Soc. Interface.

104

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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 b-catenin as the main coordinator of FSHD-associated protein interaction 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 myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/ b-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.

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Section: Introductionsupporting

confidence: 90%

Section: Meta-analysis Of Facioscapulohumeral Muscular Dystrophy Datamentioning

confidence: 99%

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

Banerji

Knopp

Moyle

et al. 2015

J. R. Soc. Interface.

104

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“…While no full DUX4 transgenic mouse has yet been published, animal models with local injection of a DUX4 expression vector have proved useful in defining its myotoxicity, with DUX4 over-expression in both zebrafish and mice inducing abnormal muscle histology and degeneration (Snider et al 2009;Wuebbles et al 2010;Wallace et al 2010). This DUX4 mediated myotoxicity can, however, be suppressed either by the introduction of mutations within the homeodomain regions, or when the DUX4 protein is over-expressed in the muscle of Tp53 knock-out mice (Wallace et al 2010).…”

Section: (A) (B) (D) (C)mentioning

confidence: 99%

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

et al. 2011

Self Cite

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Facioscapulohumeral muscular dystrophy (FS HD) is the third most common muscular dystrophy after the dystrophinopathies and myotonic dystrophy and is associated with a typical pattern of muscle weakness. Most patients with FSHD carry a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35 and present with 1-10 repeats whereas non-affected individuals possess 11-150 repeats. An almost identical repeat array is present at 10q26 and the high sequence identity between these two arrays can cause difficulties in molecular diagnosis. Each 3.3-kb D4Z4 unit contains a DUX4 (double homeobox 4) gene that, among others, is activated upon contraction of the 4q35 repeat array due to the induction of chromatin remodelling of the 4qter region. A number of 4q subtelomeric sequence variants are now recognised, although FSHD only occurs in association with three 'permissive' haplotypes, each of which is associated with a polyadenylation signal located immediately distal of the last D4Z4 unit. The resulting poly-A tail appears to stabilise DUX4 mRNAs transcribed from this most distal D4Z4 unit in FSHD muscle cells. Synthesis of both the DUX4 transcripts and protein in FSHD muscle cells induces significant cell toxicity. DUX4 is a transcription factor that may target several genes which results in a deregulation cascade which inhibits myogenesis, sensitises cells to oxidative stress and induces muscle atrophy, thus recapitulating many of the key molecular features of FSHD.

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“…Our findings have led us to consider whether p53 activation in response to chronic physiological stress occurring in myopathic diseases [21][22][23]60,61 could persistently repress myogenin and in part contribute to development of muscle atrophy at the stage of myogenic differentiation. [21][22][23][24][25][62][63][64] Moreover, we are intrigued by a possible connection between repression of myogenin by p53 and muscle aging.…”

Section: Discussionmentioning

confidence: 99%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

Cited by 222 publications

References 60 publications

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

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

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

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