The PRC2 associated factor Epop is required for Hox genes regulation during axial development in mice
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PROVIDER: PRJNA1074094 | ENA |
REPOSITORIES: ENA
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Project description:The Polycomb repressive complex 2 (PRC2) is an essential modulator of gene repression. We previously reported that in mouse embryonic stem cells (mESCs), PRC2 associates with ElonginB/C through EPOP, allowing for low-level expression of target genes. Here we investigate the role of Epop in vivo by generating a mouse knockout model: we show that Epop null mice are viable and fertile, but display highly penetrant posterior homeotic transformations of the axial skeleton. Consistently, Epop depleted embryos present a shift of the anterior boundary of expression of certain Hox genes. Tissue-specific RNA-seq in embryos suggest that the defect in Hox activation originates already at the level of the presomitic mesoderm (PSM). Overall, our findings indicate that Epop is specifically required for correct body patterning along the antero-posterior axis, by preventing premature activation of the Hox genes.
2025-08-19 | GSE255167 | GEO
Project description:Hox and Cdx transcription factors regulate embryonic positional identities. Cdx mutant mice display posterior body truncations of the axial skeleton, neuraxis, and caudal uro-rectal structures. We show that trunk Hox genes stimulate axial extension as they can largely rescue these Cdx mutant phenotypes. Conversely, posterior (paralog group 13) Hox genes can prematurely arrest posterior axial growth when precociously expressed. Our data suggest that the transition from trunk to tail Hox gene expression successively regulates construction and termination of axial structures in the mouse embryo. Thus, Hox genes seem to differentially orchestrate posterior expansion of embryonic tissues during axial morphogenesis as an integral part of their function in specifying head-to-tail identity. In addition, we present evidence that Cdx and Hox transcription factors exert these effects by controlling Wnt signaling. Concomitant regulation of Cyp26a1 expression, restraining retinoic acid signaling in the posterior growth zone, may likewise play a role in timing the trunk-tail transition.
2009-10-19 | GSE17660 | GEO
Project description:Hox and Cdx transcription factors regulate embryonic positional identities. Cdx mutant mice display posterior body truncations of the axial skeleton, neuraxis, and caudal uro-rectal structures. We show that trunk Hox genes stimulate axial extension as they can largely rescue these Cdx mutant phenotypes. Conversely, posterior (paralog group 13) Hox genes can prematurely arrest posterior axial growth when precociously expressed. Our data suggest that the transition from trunk to tail Hox gene expression successively regulates construction and termination of axial structures in the mouse embryo. Thus, Hox genes seem to differentially orchestrate posterior expansion of embryonic tissues during axial morphogenesis as an integral part of their function in specifying head-to-tail identity. In addition, we present evidence that Cdx and Hox transcription factors exert these effects by controlling Wnt signaling. Concomitant regulation of Cyp26a1 expression, restraining retinoic acid signaling in the posterior growth zone, may likewise play a role in timing the trunk-tail transition.
2009-10-19 | GSE17658 | GEO
Project description:Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential activation, the “HOX clock”, is paced by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are progenies of axial progenitors. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized access to human cells of multiple, defined, rostro-caudal identities for basic and translational applications.
2021-03-02 | GSE153519 | GEO
Project description:Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs) the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions and its mis-regulation is linked to cancer development. Here, we show that in mESCs the Polycomb Repressive Complex 2 (PRC2) associated protein EPOP (a.k.a C17orf96, esPRC2p48, E130012A19Rik) co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly up-regulated in human cancer and we demonstrate that its loss impairs the proliferation of several human cancer cell lines. Our findings establish EPOP as a unique modulator of transcriptional processes, impacting both Polycomb and active gene transcription in mammalian cells.
2016-11-17 | GSE76536 | GEO
Project description:The cellular plasticity of pluripotent stem cells is thought to be sustained by genomic regions that display both active and repressive chromatin properties. These regions exhibit low levels of gene expression, yet the mechanisms controlling these levels remain unknown. Here, we describe Elongin BC as a binding factor at the promoters of bivalent sites. Biochemical and genome-wide analysis shows that Elongin BC is associated with Polycomb Repressive Complex 2 (PRC2) in pluripotent stem cells. Elongin BC is recruited to chromatin by the PRC2-associated factor EPOP (Elongin- and POlycomb-associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a protein expressed in the inner cell mass of the mouse blastocyst. Both EPOP and Elongin BC are required to maintain low levels of expression at PRC2 genomic targets. Our results indicate that keeping the balance between activating and repressive cues is a more general feature of chromatin in pluripotent stem cells than previously appreciated.
2016-11-21 | GSE79606 | GEO
Project description:Vertebrate axial skeletal patterning is controlled by coordinated collinear expression of Hox genes and axial level-dependent activity of Hox protein combinations. Transcription factors of the Meis family act as cofactors of Hox proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning have not been established. Similarly, retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however whether this role is related to Meis/Hox regulation or functions in axial patterning remains unknown. Here we study the role of Meis factors in axial skeleton formation and its relationship to the RA pathway by characterizing Meis1, Meis2 and Raldh2 mutant mice. We report that Meis and Raldh2 regulate each other in a positive feedback regulatory loop that controls axial skeletal identity. Meis elimination produces homeotic transformations similar to those found in Raldh2 and anterior-Hox mutants and disrupts the expression of Hox target genes without changing the transcriptional profiles of Hox complexes. We propose that Meis regulates vertebrate axial skeleton patterning by exclusively affecting Hox protein function, and that alterations in RA levels can produce homeotic transformations without altering Hox transcription through regulating Meis expression.
2020-12-22 | GSE146301 | GEO
Project description:Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs) the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions and its mis-regulation is linked to cancer development. Here, we show that in mESCs the Polycomb Repressive Complex 2 (PRC2) associated protein EPOP (a.k.a C17orf96, esPRC2p48, E130012A19Rik) co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly up-regulated in human cancer and we demonstrate that its loss impairs the proliferation of several human cancer cell lines. Our findings establish EPOP as a unique modulator of transcriptional processes, impacting both Polycomb and active gene transcription in mammalian cells.
2016-11-17 | GSE85681 | GEO
Project description:Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs) the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions and its mis-regulation is linked to cancer development. Here, we show that in mESCs the Polycomb Repressive Complex 2 (PRC2) associated protein EPOP (a.k.a C17orf96, esPRC2p48, E130012A19Rik) co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly up-regulated in human cancer and we demonstrate that its loss impairs the proliferation of several human cancer cell lines. Our findings establish EPOP as a unique modulator of transcriptional processes, impacting both Polycomb and active gene transcription in mammalian cells.
2016-11-17 | GSE79318 | GEO
Project description:The axial skeleton of individual mammalian species exhibits remarkable robustness in the number and identity of vertebral elements that form(Owen 1853; Owen 1866; Narita and Kuratani 2005). Between mammalian species however, a great diversity in axial formulae has arisen due to natural selection(Narita and Kuratani 2005; Thewissen et al. 2006; Buchholtz 2007; Matsubara et al. 2017; Kingsley et al. 2017). The genetic mechanism(s) by which axial formulae in mammals is canalised, or manipulated to drive this diversity, remains a major question in biology. Here, we reveal three regulatory pathways essential in constraining total vertebral number and regional axial identity in the mouse. Specifically, the manipulation of Gdf11, Retinoic acid and microRNA-196 activity, individually and cumulatively, led to increasing total vertebral number and allowed us to understand the molecular logic constraining each major division of the vertebral column, from cervical through to tail vertebrae. All three pathways had differing control over Hox cluster expression, with heterochronic and quantitative changes in Hox expression found to parallel changes in axial identity. However, our work revealed an additional, and highly unexpected, role for Hox genes in supporting axial elongation within the tail region. This provides important support for an emerging view that mammalian Hox gene function is not limited to imparting positional identity as the mammalian body plan is laid down, and more broadly, this work provides a molecular framework with which to interrogate mechanisms of evolutionary change.
2023-08-31 | GSE157172 | GEO