Porcine DUXC and human DUX4 activate similar embryonic programs cross species: implications for preclinical model of FSHD
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE210772 | GEO | 2023/05/10
REPOSITORIES: GEO
Similar Datasets
Project description:Human DUX4 and mouse Dux transcription factors are normally expressed in the germ line and early embryonic cells where they activate the cleavage stage genes. The misexpression of DUX4 in skeletal muscles causes Facioscapulohumeral dystrophy (FSHD). In primates and rodents, DUX4 and Dux arose from retrotransposition of the mRNA from the ancestral intron-containing DUXC, which is not found in these species, and whether it has similar roles in the cleavage stage and FSHD as DUX4 and Dux are unknown. Here, we identified two isoforms of DUXC in canine testis tissues: One encodes the canonical double homeodomain (DUXC) similar to DUX4/Dux, and one contains an extra exon that disrupts the conserved amino-acid sequence of the first homeodomain (DUXC-ALT). We expressed DUXC and DUXC-ALT in canine skeletal muscle and found that the expression of DUXC induced retrotransposons and pluripotent programs similar to DUX4 and Dux, whereas DUXC-ALT did not robustly activate genes in these assays.
2021-12-03 | GSE188927 | GEO
Project description:Human DUX4 and mouse Dux transcription factors are normally expressed in the germ line and early embryonic cells where they activate the cleavage stage genes. The misexpression of DUX4 in skeletal muscles causes Facioscapulohumeral dystrophy (FSHD). In primates and rodents, DUX4 and Dux arose from retrotransposition of the mRNA from the ancestral intron-containing DUXC, which is not found in these species, and whether it has similar roles in the cleavage stage and FSHD as DUX4 and Dux are unknown. Here, we identified two isoforms of DUXC in canine testis tissues: One encodes the canonical double homeodomain (DUXC) similar to DUX4/Dux, and one contains an extra exon that disrupts the conserved amino-acid sequence of the first homeodomain (DUXC-ALT). We expressed DUXC and DUXC-ALT in canine skeletal muscle and found that the expression of DUXC induced retrotransposons and pluripotent programs similar to DUX4 and Dux, whereas DUXC-ALT did not robustly activate genes in these assays.
2021-12-03 | GSE188926 | GEO
Project description:DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.
2023-05-10 | PXD029215 | Pride
Project description:Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species. Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.
2017-02-01 | GSE87266 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species. Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.
2017-02-01 | GSE93168 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species. Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.
2017-02-01 | GSE93167 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species. Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.
2017-02-01 | GSE87279 | GEO
Project description:DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.
2022-11-01 | GSE186244 | GEO
Project description:DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.
2023-05-09 | GSE209785 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is characterised by a progressive degeneration and weakness of skeletal muscle fibers attributed to inappropriate expression of the transcription factor double homeobox 4 (DUX4). However, the cellular events that precede pathology in DUX4 expressing muscle fibers remain incompletely understood. Using recombinant AAV vectors to activate species-specific DUX transcription factors in murine and human skeletal muscle fibers, we developed models for examining DUX4-induced pathology. RNA-sequencing prior to the onset of muscle pathology reveals that perturbation of metabolic and mitochondrial function is an early event following activation of DUX transcription factors across species. A reduction in mitochondrial membrane potential was confirmed following DUX4 activation in human muscle fibers prior to reductions in force generating capacity. These studies present new models that can be used to delineate the changes in biological processes following acute DUX4 activation in mouse and human skeletal muscle fibers, for greater insight into the pathogenesis of FSHD, and support further investigation of mitochondrial function as a therapeutic target in FSHD.
2021-12-31 | GSE138768 | GEO