Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M.; Arpke, Robert W.; Baltgalvis, Kristen A.; Vang, Derek; Baik, June; Darabi, Radbod; Perlingeiro, Rita C.R.; Hamra, F. Kent; Gupta, Kalpna; Lowe, Dawn A.; Kyba, Michael

doi:10.1016/j.celrep.2014.07.056

Cited by 66 publications

(89 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DUX4 is pathogenic in both myoblasts and differentiated muscle (Vanderplanck et al, 2011; Bosnakovski et al, 2008a, 2014; Kowaljow et al, 2007; Wallace et al, 2011; Dandapat et al, 2014). Recent microarray and ChIP-seq datasets reveal that DUX4 causes wide-ranging transcriptional disruption in myogenic cells (Geng et al, 2012; Banerji et al, 2015; Rahimov et al, 2012; Knopp et al, 2016) , with its potent transcriptional activation through its C-terminal domain (Geng et al, 2012; Clapp et al, 2007; Kawamura-Saito et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Moyle

Blanc

Jaka

et al. 2016

eLife

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically-approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD.DOI: http://dx.doi.org/10.7554/eLife.11405.001

show abstract

Section: Discussionmentioning

confidence: 99%

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Moyle

Blanc

Jaka

et al. 2016

eLife

View full text Add to dashboard Cite

show abstract

“…Finally, genes downregulated by DUX4c but not DUX4 were associated with muscle development and axonal guidance. Both DUX4 and DUX4c inhibit myoblast fusion, whereas DUX4 overexpression in embryonic stem cells promotes differentiation towards the neuronal lineage (Dandapat et al, 2014), indicating that DUX4c is associated with neuronal and myogenic development in a manner that is independent of DUX4. These transcriptome signatures add to our understanding of how DUX4 and DUX4c induce pathology in FSHD.…”

Section: Discussionmentioning

confidence: 99%

“…DUX4 is expressed in germline cells, and the protein can be detected in myoblasts and muscle, but there is no overt skeletal muscle pathology (Krom et al, 2013). Ectopic DUX4 expression results in impaired myogenesis (Dandapat et al, 2014) and gross muscle damage through p53-dependent apoptosis in other mouse models (Wallace et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

Knopp

Krom

Banerji³

et al. 2016

Development

View full text Add to dashboard Cite

Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenic mice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.

show abstract

“…It is not clear whether this is due to the lack of true pathogenic targets in the mouse, a failure to recapitulate the spatiotemporal pattern of DUX4-fl expression that takes place during human development, or whether the low levels of expression in adult muscle are simply not enough to generate pathology in mice. It is encouraging that expression of DUX4-fl in another mouse model causes pathology, albeit in multiple tissues (35); presumably, a useful FSHD-like mouse model can be generated with proper regulatory mechanisms in place to ensure correct levels and timing of DUX4-fl expression. However, the fact that some asymptomatic subjects express levels of DUX4-fl similar to those of affected patients strongly suggests that FSHD requires more than a simple elevation of DUX4-fl expression in adult skeletal muscle (78).…”

Section: Therapeutic Approaches To Fshdmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

show abstract

Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

Cited by 66 publications

References 57 publications

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Contact Info

Product

Resources

About