A Non-canonical BCOR-PRC1.1 Complex Represses Differentiation Programs in Human ESCs
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ABSTRACT:
PROVIDER: PRJNA413520 | ENA |
REPOSITORIES: ENA
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Project description:Polycomb group proteins regulate self-renewal and differentiation in many stem cell systems. When assembled into two canonical complexes, PRC1 and PRC2, they sequentially deposit H3K27me3 and H2AK119ub histone marks and establish repressive chromatin, referred to as Polycomb domains. Non-canonical PRC1 complexes retain RING1/ RNF2 E3-ubiquitin ligases but have unique sets of accessory subunits. How these non-canonical complexes recognize and regulate their gene targets remains poorly understood. Here, we show that the BCL6 co-repressor (BCOR), a member of the PRC1.1 complex, is critical for maintaining primed pluripotency in human embryonic stem cells (ESCs). BCOR depletion leads to the erosion of Polycomb domains at key developmental loci and the initiation of differentiation along endoderm and mesoderm lineages. The C terminus of BCOR regulates the assembly and targeting of the PRC1.1 complex, while the N terminus contributes to BCOR-PRC1.1 repressor function. Our findings advance understanding of Polycomb targeting and repression in ESCs and could apply broadly across developmental systems.
2018-01-11 | GSE104690 | GEO
Project description: Not available
| S-EPMC5797497 | biostudies-literature
Project description:Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a non-canonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1 mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor suppressive activity and identifies a therapeutic strategy in PRC1.1 mutated cancer.
2022-02-28 | GSE167869 | GEO
Project description:Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here we find that the non-canonical PRC1.1 complex, as identified by mass spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is co-targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3 suggesting a gene regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls distinct gene clusters involved in unique cell biological processes required for leukemic cell viability. K562 cells were transduced with lentiviral GFP-fusion vectors encoding GFP-CBX2, PCGF1-GPF, PCGF2-GFP, PCGF4-GFP, GFP-RING1A or GFP-RING1B. K562 cells expressing GFP-fusions at relatively low levels were sorted and expanded and subsequently crosslinked. ChIP reactions were performed using the following antibodies: anti-GFP (ab290, Abcam), anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), and anti-KDM2B (ab137547, Abcam). Furthermore, ChIP reactions were performed using primary AML CD34+ and Peripheral Blood (PB) CD34+ cells using anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), anti-KDM2B (ab137547, Abcam).
2015-11-24 | E-GEOD-54580 | biostudies-arrayexpress
Project description:In an attempt to unravel the functionality and targettability of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we dissected the subunit composition of the PRC1.1 complex and show that USP7 and TRIM27 are integral components. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H3K4me3 levels remain unaffected. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in (primary) AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is significantly delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.
2021-06-14 | PXD018365 | Pride
Project description:Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here we find that the non-canonical PRC1.1 complex, as identified by mass spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is co-targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3 suggesting a gene regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls distinct gene clusters involved in unique cell biological processes required for leukemic cell viability.
2015-11-24 | GSE54580 | GEO
Project description:CD4+ T helper 17 (Th17) cells protect vertebrate hosts from extracellular pathogens at mucosal surfaces. Th17 cells form from naïve precursors when signals from the T cell antigen receptor (TCR) and certain cytokine receptors induce the expression of the RORγt transcription factor, which activates a set of Th17-specific genes. Using T cell-specific loss-of-function experiments we find that two components of the Polycomb Repressive Complex 1.1 (PRC1.1), BCL6 corepressor (BCOR) and KDM2B, which helps target the complex to unmethylated CpG DNA islands, are required for optimal Th17 cell formation in mice after Streptococcus pyogenes infection. Genome-wide expression and BCOR chromatin immunoprecipitation studies revealed that BCOR directly represses Lef1, Runx2, and Dusp4, whose products inhibit Th17 differentiation. Together, the results suggest that PRC1.1 components, BCOR and KDM2B, work together to enhance Th17 cell formation by repressing Th17 fate suppressors.
2019-04-26 | GSE121766 | GEO
Project description:BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes
| PRJNA705362 | ENA
Project description:The identification of subtype-specific translocations has revolutionized diagnostics of sarcoma and provided new insight into oncogenesis. We used RNA-Seq to investigate samples diagnosed as small round cell tumors of bone, possibly Ewing sarcoma, but lacking the canonical EWSR1-ETS translocation. A new fusion was observed between the BCL6 co-repressor (BCOR) and the testis specific cyclin B3 (CCNB3) genes on chromosome X. RNA-Seq results were confirmed by RT-PCR and cloning the tumor-specific genomic translocation breakpoints. 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcomas. Gene profiling experiments indicate that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly EwingM-bM-^@M-^Ys sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this group of sarcoma and that over-expression of BCOR-CCNB3 or of a truncated CCNB3 activates S-phase in NIH3T3 cells. Thus the intrachromosomal X fusion described here represents a new subtype of bone sarcoma caused by a novel gene fusion mechanism. Comparison of expression profiles of 10 BCOR-CCNB3 samples (plus 4 EWS-FLI1 Ewing sarcomas samples as control) with publicly available profiles of other tumor types.
2012-03-03 | E-GEOD-34800 | biostudies-arrayexpress
Project description:The identification of subtype-specific translocations has revolutionized diagnostics of sarcoma and provided new insight into oncogenesis. We used RNA-Seq to investigate samples diagnosed as small round cell tumors of bone, possibly Ewing sarcoma, but lacking the canonical EWSR1-ETS translocation. A new fusion was observed between the BCL6 co-repressor (BCOR) and the testis specific cyclin B3 (CCNB3) genes on chromosome X. RNA-Seq results were confirmed by RT-PCR and cloning the tumor-specific genomic translocation breakpoints. 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcomas. Gene profiling experiments indicate that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing’s sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this group of sarcoma and that over-expression of BCOR-CCNB3 or of a truncated CCNB3 activates S-phase in NIH3T3 cells. Thus the intrachromosomal X fusion described here represents a new subtype of bone sarcoma caused by a novel gene fusion mechanism.
2012-03-03 | GSE34800 | GEO