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Canine DUXC isoforms and functional similarity to human DUX4 [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE188926 | GEO | 2021/12/03

REPOSITORIES: GEO

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Canine DUXC isoforms and functional similarity to human DUX4 [RNA-seq]

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

Porcine DUXC and human DUX4 activate similar embryonic programs cross species: implications for preclinical model of FSHD

Project description:DUX4 and its mouse ortholog Dux are normally expressed in the early embryo—the 4 cell or 2 cell cleavage stage embryo, respectively—and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas FSHD-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program, and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a pre-clinical model for FSHD. In this study, we identify the porcine DUXC mRNA expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.

2023-05-10 | GSE210772 | GEO

Conservation and innovation in the DUX4-family gene network [MMH6 ChIP-Seq]

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

Conservation and innovation in the DUX4-family gene network (ChIP-seq)

2017-02-01 | GSE87279 | GEO

Conservation and innovation in the DUX4-family gene network (RNA-seq)

2017-02-01 | GSE87266 | GEO

Conservation and innovation in the DUX4-family gene network [MMH6 RNA-Seq]

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LC-MS of FLAG-tagged C-terminal domain of human DUX4

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

Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein

Project description:Double homeobox genes are unique to eutherian mammals, transiently expressed in early blastomere-stage embryos, and comprise 3 clades (DUXA, B, and C) evolved by homeodomain duplication and divergence from an ancestral single homeobox gene, sDUX, present in non-eutherian mammals and other vertebrates. We test platypus sDUX and find that it drives cellular phenotypes identical to DUX4, the human DUXC gene, including cytotoxicity and inhibition of myogenic differentiation. sDUX binds DNA as a head-to-head dimer, showing near overlap of protein core and DNA to the DUX4-DNA crystal structure. DUXA and sDUX bind both palindromic and nonpalindromic TAAT/TGAT double homeodomain motifs against DUX4 preference for non-palindromic. Although DUXA lacks transcriptional activation potential, we find significant similarities in transcriptional and chromatin profiles of sDUX with DUX4 and DUXA-VP64, including expression of ZGA genes and LTR elements. Furthermore, DUXA binds to a significant fraction of DUX4 target sites and is able to counteract transcriptional activation of DUX4 on its targets, potentiating a feedback inhibitory loop, including in cells from patients with facioscapulohumeral muscular dystrophy (FSHD). The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.

2023-02-08 | GSE214245 | GEO

Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein II

Project description:Double homeobox genes are unique to eutherian mammals, transiently expressed in early blastomere-stage embryos, and comprise 3 clades (DUXA, B, C) evolved by homeobox duplication and divergence from an ancestral single homeobox gene, sDUX, present in other vertebrates. We test platypus sDUX and find that it drives cytotoxicity and inhibition of myogenesis identical to DUX4, the human DUXC gene. sDUX binds DNA as a head-to-head dimer, with protein core and DNA nearly overlapping the DUX4-DNA crystal structure. Although DUXA lacks transcriptional activity, DUXA-VP64 transcriptome and chromatin accessibility profiles significantly overlap those of DUX4 and sDUX, including expression of ZGA genes and LTR elements. Furthermore, DUXA binds DUX4 sites at most DUX4 target genes and counteracts transcriptional activity of DUX4, including in FSHD patient cells, potentiating a feedback inhibitory loop. The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.

2023-02-08 | GSE214229 | GEO

Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein I

2023-02-08 | GSE214228 | GEO

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