Double homeobox gene, Duxbl, promotes myoblast proliferation and abolishes myoblast differentiation by blocking MyoD transactivation

Wu, Shey Lin; Li, Guo Zili; Chou, Chin Yi; Tsai, Ming-Shiun; Chen, Yi Pei; Li, Chung Jung; Liou, Gunn‐Guang; Chang, Wen‐Wei; Chen, Shen Liang; Wang, Sue-Hong

doi:10.1007/s00441-014-1974-x

“…Myog levels increased during the early phase of muscle regeneration in both D4Z4-2.5 and D4Z4-12.5 mice as expected. As shown previously (Wu et al, 2014), substantial Duxbl levels were detectable in mouse skeletal muscle, with levels enhanced during regeneration ().…”

Section: Resultssupporting

confidence: 80%

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

Knopp

¹

,

Krom

²

,

Banerji³

et al. 2016

Journal of Cell Science

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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.

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“…Myog levels increased during the early phase of muscle regeneration in both D4Z4-2.5 and D4Z4-12.5 mice as expected. As shown previously (Wu et al, 2014), substantial Duxbl levels were detectable in mouse skeletal muscle, with levels enhanced during regeneration (Fig. S1A,B).…”

Section: Dux4 Is Transiently Expressed During Skeletal Muscle Regenersupporting

confidence: 86%

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

Knopp

¹

,

Krom

²

,

Banerji³

et al. 2016

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.

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“…However, increasing Duxbl plasmid concentrations still failed to induce cell death (data not shown), and previous in vitro over-expression studies with Duxbl suggested it promoted cell proliferation and likewise did not stimulate cell death (Fig. 2B) (35). We performed identical experiments in HEK293s using several cell viability/cell death assays including quantifying caspase 3/7 activity and trypan blue exclusion counts.…”

Section: Resultssupporting

confidence: 58%

Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4

Eidahl

¹

,

Giesige

²

,

Domire

³

et al. 2016

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D4Z4 repeats are present in at least 11 different mammalian species, including humans and mice. Each repeat contains an open reading frame encoding a double homeodomain (DUX) family transcription factor. Aberrant expression of the D4Z4 ORF called DUX4 is associated with the pathogenesis of Facioscapulohumeral muscular dystrophy (FSHD). DUX4 is toxic to numerous cell types of different species, and over-expression caused dysmorphism and developmental arrest in frogs and zebrafish, embryonic lethality in transgenic mice, and lesions in mouse muscle. Because DUX4 is a primate-specific gene, questions have been raised about the biological relevance of over-expressing it in non-primate models, as DUX4 toxicity could be related to non-specific cellular stress induced by over-expressing a DUX family transcription factor in organisms that did not co-evolve its regulated transcriptional networks. We assessed toxic phenotypes of DUX family genes, including DUX4, DUX1, DUX5, DUXA, DUX4-s, Dux-bl and mouse Dux. We found that DUX proteins were not universally toxic, and only the mouse Dux gene caused similar toxic phenotypes as human DUX4. Using RNA-seq, we found that 80% of genes upregulated by Dux were similarly increased in DUX4-expressing cells. Moreover, 43% of Dux-responsive genes contained ChIP-seq binding sites for both Dux and DUX4, and both proteins had similar consensus binding site sequences. These results suggested DUX4 and Dux may regulate some common pathways, and despite diverging from a common progenitor under different selective pressures for millions of years, the two genes maintain partial functional homology.

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Double homeobox gene, Duxbl, promotes myoblast proliferation and abolishes myoblast differentiation by blocking MyoD transactivation

Cited by 9 publications

References 64 publications

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

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

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

Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4

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