Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85935 | GEO | 2016/08/24
SECONDARY ACCESSION(S): PRJNA339785
REPOSITORIES: GEO
Similar Datasets
Project description:We report the RNA-seq experiments performed in human myoblasts transfected with human DUX4 and mouse Dux. Comparison of genes up- and down-regulated by DUX4 and Dux in human myoblasts to identify pathways similiarly regulated by both transcription factors.
2016-08-24 | E-GEOD-85935 | biostudies-arrayexpress
Project description:We report both DUX4 and Dux toxicity depend upon their ability to bind DNA and activate transcription. Chromatin immunoprecipitation of V5 epitope tagged human DUX4 and mouse Dux was performed in human myoblasts was analyzed using ChIP-Seq to identify their subsequent binding sites. We found that DUX4 and Dux bind 4-8% of identical sequences, while majority of the binding sites are unique to either DUX4 or Dux. Although small, this overlap could be due to their conserved abilioty to regualte primordial pathways that were essential for life and therefore maintained in both proteins despite their separate evolutionary paths. We performed ChIP-Seq analysis of human myoblasts transfected with plasmids encoding either epitope tagged human DUX4 (1 sample) and mouse Dux (1 sample). Illumina sequencing libraries were prepared from the ChIP and Input DNA, then resulting DNA libraries were quantified and sequenced and aligned to the human genome (hg19).
2015-12-11 | E-GEOD-75791 | biostudies-arrayexpress
Project description: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.
| S-EPMC5409219 | biostudies-literature
Project description:We report both DUX4 and Dux toxicity depend upon their ability to bind DNA and activate transcription. Chromatin immunoprecipitation of V5 epitope tagged human DUX4 and mouse Dux was performed in human myoblasts was analyzed using ChIP-Seq to identify their subsequent binding sites. We found that DUX4 and Dux bind 4-8% of identical sequences, while majority of the binding sites are unique to either DUX4 or Dux. Although small, this overlap could be due to their conserved abilioty to regualte primordial pathways that were essential for life and therefore maintained in both proteins despite their separate evolutionary paths.
2015-12-11 | GSE75791 | 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: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.
2023-05-09 | GSE209785 | GEO
Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. [Overexpression experiment] Quadruplicate total RNA samples were collected from control human primary myoblasts transduced with lentivirus carrying DUX4-fl, DUX4-s or GFP (MOI = 15) for 24 h and from untransduced myoblasts. [Defensin experiment] Quadruplicate samples were also collected from myoblasts and myotubes grown in media containing human beta-defensin 3 peptide or in control media.
2012-01-03 | E-GEOD-33799 | biostudies-arrayexpress
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