Similar Datasets
Project description:Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer when misexpressed. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 cytotoxicity is not shared with DUXA or DUXB, but surprisingly is shared with platypus sDUX, which binds DNA as a homodimer and activates numerous ZGA genes and long terminal repeat (LTR) elements. DUXA, although transcriptionally inactive, has DNA binding overlap with DUX4, and DUXA-VP64 activates DUX4 targets and is cytotoxic. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is a DUX4 target gene, this competition potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises antagonistic members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.
| S-EPMC10514451 | biostudies-literature
Project description:Double homeobox (DUX) genes are unique to eutherian mammals and normally expressed transiently during zygotic genome activation. The canonical member, DUX4, is involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer, when misexpressed in other contexts. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 activities are not shared with DUXA or DUXB, which lack transcriptional activation potential, but surprisingly are shared with platypus sDUX. In human myoblasts, platypus sDUX drives cytotoxicity, inhibits myogenesis, and induces DUX4 target genes, particularly those associated with zygotic genome activation (ZGA), by binding DNA as a homodimer in a way that overlaps the DUX4 homeodomain crystal structure. DUXA lacks transcriptional activity but has DNA-binding and chromatin accessibility overlap with DUX4 and sDUX, including on ZGA genes and LTR elements, and can actually be converted into a DUX4-like cytotoxic factor by fusion to a synthetic transactivation domain. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is an early DUX4 target gene, this activity potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.HighlightsPlatypus sDUX is toxic and inhibits myogenic differentiation.DUXA targets overlap substantially with those of DUX4.DUXA fused to a synthetic transactivation domain acquires DUX4-like toxicity.DUXA behaves as a competitive inhibitor of DUX4.
| S-EPMC9882399 | biostudies-literature
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
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
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
Project description:Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein
| PRJNA884482 | ENA
Project description:Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein
| PRJNA884400 | ENA
Project description:Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein I
| PRJNA884408 | ENA
Project description:Evolution of antagonism among DUX family members from an ancestral toxic single homeodomain protein II
| PRJNA884407 | ENA
Project description:E2F is a heterogenous transcription factor and its role in cell cycle control results from the integrated activities of many different E2F family members. Unlike mammalian cells, that have a large number of E2F-related genes, the Drosophila genome encodes just two E2F genes, de2f1 and de2f2. Here we show that de2f1 and de2f2 provide different elements of E2F regulation and that they have opposing functions during Drosophila development. dE2F1 and dE2F2 both heterodimerize with dDP and bind to the promoters of E2F-regulated genes in vivo. dE2F1 is a potent activator of transcription, and the loss of de2f1 results in the reduced expression of E2F-regulated genes. In contrast, dE2F2 represses the transcription of E2F reporters and the loss of de2f2 function results in increased and expanded patterns of gene expression. The loss of de2f1 function has previously been reported to compromise cell proliferation. de2f1 mutant embryos have reduced expression of E2F-regulated genes, low levels of DNA synthesis, and hatch to give slow-growing larvae. We find that these defects are due in large part to the unchecked activity of dE2F2, since they can be suppressed by mutation of de2f2. Examination of eye discs from de2f1; de2f2 double-mutant animals reveals that relatively normal patterns of DNA synthesis can occur in the absence of both E2F proteins. This study shows how repressor and activator E2Fs are used to pattern transcription and how the net effect of E2F on cell proliferation results from the interplay between two types of E2F complexes that have antagonistic functions.
| S-EPMC312757 | biostudies-literature