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Assessment of functional overlap between mouse Dux and human DUX4 in vitro and in vivo

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75791 | GEO | 2015/12/11

SECONDARY ACCESSION(S): PRJNA305358

REPOSITORIES: GEO

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Assessment of functional overlap between mouse Dux and human DUX4 in vitro and in vivo

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

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

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

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

Project description:We report the RNA-seq experiments performed in human myoblasts transfected with human DUX4 and mouse Dux.

2016-08-24 | GSE85935 | GEO

Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction

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

Canine DUXC isoforms and functional similarity to human DUX4 [ChIP-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 | GSE188926 | GEO

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

2021-12-03 | GSE188927 | GEO

Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction [CUT&TAG]

2023-05-09 | GSE209785 | GEO

Retroelements and DUX4 Create Primate-specific Promoters for Germline Genes

Project description:The human double-homeodomain retrogene DUX4 is normally expressed at high levels in germ cells of the testis. When aberrantly expressed in muscle its protein product causes facioscapulohumeral muscular dystrophy (FSHD), perhaps partly by inducing inappropriate expression of germline genes. DUX4 can bind >60,000 locations in the human genome that contain a strongly enriched sequence motif. Numerous long terminal repeat (LTR) class repetitive elements are enriched among DUX4 binding sites, including many from the mammalian apparent LTR-retrotransposon (MaLR) family as well as some ERVL and ERVK types, with MaLRs comprising ~1/3 of DUX4’s binding sites. We performed RNA-seq on myoblasts over-expressing DUX4 and find that DUX4 binding activates transcription of some but not all bound repeat types. Some of these activated repetitive elements comprise novel promoters for genes, long non-coding RNAs and antisense transcripts. We show that some of these chimeric repeat-initiated transcripts are expressed in testis and FSHD patient myotubes. The acquisition of MaLR-LTR elements during mammalian evolution may therefore have allowed rewiring of the transcriptional network. We also find that the pericentromeric satellite HSATII can be bound by DUX4 and that its transcription is massively induced by DUX4 over-expression. Our findings suggest a role for repetitive element transcripts in muscle disease and in the biology of normal testis. RNA-seq of two myoblast cell lines transduced with lentivirus carrying DUX4, and two control myoblast lines

2013-10-01 | E-GEOD-45883 | biostudies-arrayexpress

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