Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A family of double-homeodomain transcription factors promotes zygotic genome activation in placental mammals [RNA-seq]

ABSTRACT: In metazoans, the fertilized embryo is transcriptionally mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio but their mammalian homologues are still undefined. Here, we reveal that DUX family transcription factors are key to this process in human and mouse. First, human Dux4 and murine Dux are expressed prior to ZGA in both species. Second, both orthologues bind to and activate the promoters of ZGA genes. Third, Dux knockdown hinders the progression of mouse embryos beyond the 2-cell stage. Fourth, it prevents the cycling of mouse embryonic stem (ES) cells through a 2-cell-like state whereas, conversely, Dux overexpression induces the accumulation of these ZGA genes-expressing ES cells. We conclude that DUX proteins are master regulators of mammalian ZGA.

ORGANISM(S): Mus musculus

PROVIDER: GSE94324 | GEO | 2017/03/23

SECONDARY ACCESSION(S): PRJNA369392

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A family of double-homeodomain transcription factors promotes zygotic genome activation in placental mammals [ChIP-seq_d2]

Project description:In metazoans, the fertilized embryo is transcriptionally mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio but their mammalian homologues are still undefined. Here, we reveal that DUX family transcription factors are key to this process in human and mouse. First, human Dux4 and murine Dux are expressed prior to ZGA in both species. Second, both orthologues bind to and activate the promoters of ZGA genes. Third, Dux knockdown hinders the progression of mouse embryos beyond the 2-cell stage. Fourth, it prevents the cycling of mouse embryonic stem (ES) cells through a 2-cell-like state whereas, conversely, Dux overexpression induces the accumulation of these ZGA genes-expressing ES cells. We conclude that DUX proteins are master regulators of mammalian ZGA.

2017-03-23 | GSE94323 | GEO

A family of double-homeodomain transcription factors promotes zygotic genome activation in placental mammals [ChIP-seq_d1]

2017-03-23 | GSE94322 | GEO

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

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 | GSE214228 | GEO

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

2023-02-08 | GSE214229 | GEO

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

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

Dux cluster duplication ensures fully activation of totipotent genes

Project description:Mammalian zygotic genome activation (ZGA) following fertilization refers to the process that results in transcriptional awakening of the embryonic genome at two-cell (2C) stage in mice or 4-8 cell stage in human. ZGA confers to the mouse 2C embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL transposons. Intriguingly, many ZGA-related totipotent genes are duplicated and clustered in the genome during evolution, including Dux cluster, OBOX and Zscan4 family members in mice. Yet, the contribution and biological significance of the totipotency-related gene duplication events during evolution in totipotency acquisition remain poorly understood. Here, we focus on Dux cluster, the master regulator of ZGA that is necessary and sufficient for the emergence of 2C-like cells (2CLCs) and activation of target totipotent genes in mouse embryonic stem cells (ESCs). By reducing Dux gene copy number from 31 to 0 or 1 with CRISPR-Cas9 technology, we generated Dux-KO and Dux (n=1) ES cell lines, respectively. We found that the totipotent gene transcriptional profile could not be fully activated in Dux (n=1) mESCs compared to wild type (WT) mESCs after treatment with DNMT1 protein degrader, mimicking the DNA demethylation process during early embryo development. These data demonstrate that Dux cluster duplication is essential for fully activation of totipotency-related genes, ensuring ZGA and totipotency acquisition.

2024-10-12 | GSE263217 | GEO

Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice III

Project description:In mammalian embryos, Dux transcription factors (TF) drive a cleavage stage-specific transcriptional burst associated with zygotic genome activation (ZGA) during which hundreds of genes and endogenous retroviral (ERV) elements are transiently expressed. In mice, ZGA begins in late 1-cell (1C) embryos and is shut down within hours at the late 2-cell (2C) to 4-cell (4C) stage. While this transition is accompanied by the loss of totipotency, it is not clear whether shutdown of Dux-induced ZGA is required for this process and how ZGA is terminated. Here, we reveal an essential negative feedback axis by which the Dux family member Duxbl terminates Dux-induced ZGA from the mid 2C stage onward by direct suppression of genomic Dux target loci. Consequently, Duxbl inactivation results in sustained expression of Dux-induced ZGA leading to 4C arrest. Our study reveals the Dux/Duxbl axis that determines the timing of totipotency exit enabling the very first divergence of cell fates.

2023-12-07 | GSE213702 | GEO

Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice II

2023-12-07 | GSE213701 | GEO