Mus musculus
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ABSTRACT:
PROVIDER: PRJNA149825 | ENA |
REPOSITORIES: ENA
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Project description:Polycomb group proteins are transcriptional repressors that control cell identity and development. In mammals, at least five different CBX proteins are believed to associate with the core Polycomb repressive complex 1 (PRC1). CBX6 and CBX7 are the most highly expressed CBX proteins in embryonic stem cells (ESCs), yet little is known about the function of CBX6 in these cells. Here we show that CBX6 is an essential regulator of ESC identity, since ablation of CBX6 function destabilizes the pluripotency network and triggers differentiation. At the molecular level, CBX6 is linked to the canonical PRC1 (cPRC1) complex; however, contrary to expectations, our results indicate that CBX6 also has a non-canonical PRC1 function. Taken together, our findings reveal that CBX6 is an essential component for ESC biology and contributes to the structural and functional complexity of the PRC1 complex.
2017-09-25 | PXD007577 | Pride
Project description:The CBX family of proteins is central to proper mammalian development via key roles in Polycomb-mediated maintenance of repression. CBX proteins in differentiated lineages have chromatin compaction and phase separation activities that might contribute to maintaining repressed chromatin. The predominant CBX protein in pluripotent cells, CBX7, lacks the domain required for these activities. We inserted this functional domain into CBX7 in embryonic stem cells to test the hypothesis that it contributes a key epigenetic function. ESCs expressing this chimeric CBX7 were impaired in their ability to properly form embryoid bodies and neural progenitor cells and showed reduced activation of lineage-specific genes across differentiation. Neural progenitors exhibited a corresponding inappropriate maintenance of Polycomb binding at neural-specific loci over the course of differentiation. We propose that a switch in the ability to compact and phase separate is a central aspect of Polycomb group function during the transition from pluripotency to differentiated lineages.
2021-10-11 | GSE151900 | GEO
Project description:The CBX family of proteins is central to proper mammalian development via key roles in Polycomb-mediated maintenance of repression. CBX proteins in differentiated lineages have chromatin compaction and phase separation activities that might contribute to maintaining repressed chromatin. The predominant CBX protein in pluripotent cells, CBX7, lacks the domain required for these activities. We inserted this functional domain into CBX7 in embryonic stem cells to test the hypothesis that it contributes a key epigenetic function. ESCs expressing this chimeric CBX7 were impaired in their ability to properly form embryoid bodies and neural progenitor cells and showed reduced activation of lineage-specific genes across differentiation. Neural progenitors exhibited a corresponding inappropriate maintenance of Polycomb binding at neural-specific loci over the course of differentiation. We propose that a switch in the ability to compact and phase separate is a central aspect of Polycomb group function during the transition from pluripotency to differentiated lineages.
2021-10-11 | GSE151899 | GEO
Project description:Polycomb group proteins are transcriptional repressors that control cell identity and development. In mammals, at least five different CBX proteins are believed to associate with the core Polycomb repressive complex 1 (PRC1). CBX6 and CBX7 are the most highly expressed CBX proteins in embryonic stem cells (ESCs), yet little is known about the function of CBX6 in these cells. Here we show that CBX6 is an essential regulator of ESC identity, since ablation of CBX6 function destabilizes the pluripotency network and triggers differentiation. At the molecular level, CBX6 is linked to the canonical PRC1 (cPRC1) complex; however, contrary to expectations, our results indicate that CBX6 also has a non-canonical PRC1 function. Taken together, our findings reveal that CBX6 is an essential component for ESC biology and contributes to the structural and functional complexity of the PRC1 complex.
2017-09-15 | GSE98723 | GEO
Project description:The Polycomb Group Proteins (PcG) are epigenetic regulatory complexes, dysregulation of which has been associated with multiple biological processes, including maintenance of cell identity, differentiation, proliferation, and cancer progression.PcGs form two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and PRC2(1).The PRC2 protein complex mainly consists of Early embryonic deficient (EED), Suppressor of Zeste (SUZ12) and Enhancer of Zeste (EZH), which can catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3), thereby leaving a transcriptionally repressive mark on the chromatin . Such alterations are recognized and read by canonical PRC1 which is composed of CBX (polycomb), PCGF (polycomb group factor), HPH (human polyhomeotic homolog), and the E3-ligase protein (RING) that catalyzes the monoubiquitination of histone H2A on lysine 119 (H2AK119ub1). The H3K27me3 mark is identified by and binds to the chromodomain within the CBX protein in PRC1, thereby ubiquitinating H2AK119 via the RING proteins. The interaction of PRC2 and PRC1 in chromatin contributes to chromatin compaction and transcriptional silencing of target genes.There are five chromobox proteins in humans, CBX2, 4, 6, 7 and 8. Increasing evidence supports essential roles of CBX proteins in tumorigenesis. Remarkably, CBX proteins have shown an opposite function in distinct cancer types in tumor development. For example, CBX7 is overexpressed in ovarian and prostate cancer , implying its oncogenic role in these tumor types. In contrast, CBX7 functions as a tumor suppressor and loss of CBX7 has been associated with increasing the malignancy grade in bladder, breast, pancreatic, glioma, and colon carcinomas (3 4 5 6 7), but its tumor suppression mechanism is unclear.
2021-06-15 | GSE158244 | GEO
Project description:Leukemias are characterized by bone marrow failure due to oncogenic mutations of hematopoietic stem cells (HSC) or blood precursor cells. HSC differentiation and self-renewal properties are tightly regulated by Polycomb group (PcG) proteins, a well-characterized family of transcriptional epigenetic regulators. PcG proteins form two canonical complexes: Polycomb repressive complex 1 (PRC1), and Polycomb repressive complex 2 (PRC2).CBX proteins link the activity of PRC1 with PRC2, serving as critical regulators of PcG-mediating activity. While the functional role of some CBX proteins in cancer has been largely explored, recent reports support the specific role of CBX2 in human tumors, thus it represent a promising new target for anti-cancer strategies. To date, chromodomain inhibitors have been identified for CBX7 , but no molecules inhibiting CBX2 have been described. Nevertheless, different chromatin-modulating drugs such as histone deacetylase inhibitors (HDACi) are reported to regulate CBX2 targets on chromatin, suggesting that HDACi might be used to indirectly modulate aberrant effects of CBX2 in cancer. We describe a novel SAHA-mediated mechanism of CBX2 post-translational regulation. We found that CBX2 undergoes SAHA-induced SUMO2/3 modification and that CBX2 SUMOylation promotes its ubiquitination and proteasome-dependent degradation. We also identified the specific molecular pathway and key players regulating CBX2 stability, demonstrating that CBX4 and RNF4 act as the E3 SUMO and E3 ubiquitin ligase, respectively. Additionally, CBX2-depleted leukemic cells display impaired proliferation, showing that CBX2 is required for leukemia cell clonogenicity. Our study provides the first evidence of a non-canonical SAHA-mediated anti-tumorigenic activity via CBX2 SUMOylation and degradation
2018-02-27 | PXD008287 | Pride
Project description:Chromobox (CBX) family proteins are components in polycomb repressive complex 1 (PRC1), responsible for targeting PRC1 to the chromatin. We studied genes regulated by CBX6, 7, or 8 in human ACC-Meso-4 mesothelioma cell line by microarray analysis of ACC-Meso-4 cells stably expressing short hairpin RNA (shRNA) targeting CBX-6, 7, 8, or control nontarget shRNA.
2019-02-22 | GSE126605 | GEO
Project description:The family of Heterochromatin Protein 1 (HP1) consists of highly conserved proteins, which have important functions in the nucleus of eukaryotic cells. In mammals there are three HP1 paralogs: HP1(alpha), Hp1(beta), and Hp1(gamma)They are encoded by the Cbx5, Cbx1, and Cbx3 genes, respectively. Hp1 and Hp1 stably interact with Chd4 and Adnp to form the ChAHP complex. In this project, Chd4, Adnp, and the three Cbx genes were endogenously tagged with a FLAG-Avi tag in mouse embryonic stem cells. The tagged proteins were subjected to tandem-affinity purification and analysis by mass spectrometry.
2018-05-22 | PXD006226 | Pride
Project description:Polycomb group (PcG) proteins comprise a large group of evolutionary conserved factors with essential roles for embryonic development and adult stem cell function. PcG proteins constitute two main multiprotein polycomb repressive complexes (PRC1 and PRC2) that operate in a hierarchical manner to silence gene expression. Functionally distinct PRC1 complexes are defined by Polycomb group RING finger protein (PCGF) paralogs. So far, six PCGF paralogs (PCGF1-6) have been identified but paralog-specific functions are not well understood. In our studies, we observed that Pcgf6 showed the highest expression level in undifferentiated murine embryonic stem cells (ESCs), blastocysts and testes. When ESCs differentiated, Pcgf6 expression strongly declined. To further investigate Pcgf6 biology, we established dox-inducible shRNA knockdown (KD) ESCs. Following Pcgf6 KD in ESCs the expression of pluripotency genes decreased, while mesodermal- and spermatogenesis-specific genes were de-repressed. Concomitantly with the elevated expression of mesodermal lineage markers, Pcgf6 KD ESCs showed increased hemangioblastic and hematopoietic activities. Finally, PCGF6 replaced SOX2 but not KLF4 or c-MYC in the generation of germline-competent iPS cells. Forced expression of Pcgf6 in OSKM-driven reprogramming increases iPS efficiency while Pcgf6 KD reduces the formation of ESC-like colonies. Together, these analyses show that Pcgf6 is non-redundantly involved in maintaining the pluripotent nature of ESCs and functions in iPS reprogramming. 6 samples were hybridized GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix)
2014-09-26 | E-GEOD-56126 | biostudies-arrayexpress
Project description:Canonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.
2022-01-03 | GSE182592 | GEO