THE POLYCOMB PROTEINS RING1B AND EZH2 REPRESS THE TUMORAL PROINFLAMMATORY FUNCTION IN METASTASIZING PRIMARY CUTANEOUS SQUAMOUS CELL CARCINOMA
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ABSTRACT:
PROVIDER: PRJNA428288 | ENA |
REPOSITORIES: ENA
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Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epigenetic regulation of gene expression may allow tumoral cells to acquire new functions in order to escape from the primary tumor. The aim of this study was to investigate the expression and function of proteins of the Polycomb family of epigenetic regulators in the metastatic process of cSCC. A higher expression of RING1B and EZH2 was detected by immunohistochemistry in a series of primary cSCC tumors that metastasized (MSCC) when compared to non metastasizing cSCC (non MSCC). Stable downregulation of RING1B and EZH2 in cSCC cells results in enhanced expression of inflammatory cytokines and activation of the NFκB signaling pathway. Accordingly, non MSCC display higher levels of membranous pS176 IKK and their stroma is enriched in neutrophils and eosinophils when compared to MSCC. In vitro, hematopoietic cells exhibit a substantial migratory response to supernatants from Polycomb depleted cSCC cells. Altogether these data indicate that RING1B and EZH2 repress the innate inflammatory cSCC function and impair tumor immunosurveillance and suggest that patients with high risk cSCC could benefit from clinical therapies addressed to harness the immune response.
2018-06-04 | GSE108682 | GEO
Project description:Native ChIP on chip for H3K27me3 in murine ES cells comparing WT and Ring1B-/- cells. Paper Abstract: How polycomb group proteins repress gene expression in vivo is not known. Whilst histone modifying activities of the polycomb repressive complexes have been studied extensively, in vitro data has suggested a direct activity of the PRC1 complex in compacting chromatin. Here, we investigate higher-order chromatin compaction of polycomb targets in vivo. We show that polycomb repressive complexes are required to maintain a compact chromatin state at Hox loci in embryonic stem (ES) cells. There is specific decompaction in the absence of PRC2 or PRC1. This is due to PRC1, since decompaction occurs in Ring1B null cells that still have PRC2-mediated H3K27 methylation. Moreover, we show that the ability of Ring1B to restore a compact chromatin state, and to repress Hox gene expression in ES cells, is not dependent on its histone ubiquitination activity. We suggest that Ring1B-mediated chromatin compaction acts to directly limit transcription in vivo.
2010-05-14 | GSE20213 | GEO
Project description:Native ChIP on chip for H3K27me3 in murine ES cells comparing WT and Ring1B-/- cells. Paper Abstract: How polycomb group proteins repress gene expression in vivo is not known. Whilst histone modifying activities of the polycomb repressive complexes have been studied extensively, in vitro data has suggested a direct activity of the PRC1 complex in compacting chromatin. Here, we investigate higher-order chromatin compaction of polycomb targets in vivo. We show that polycomb repressive complexes are required to maintain a compact chromatin state at Hox loci in embryonic stem (ES) cells. There is specific decompaction in the absence of PRC2 or PRC1. This is due to PRC1, since decompaction occurs in Ring1B null cells that still have PRC2-mediated H3K27 methylation. Moreover, we show that the ability of Ring1B to restore a compact chromatin state, and to repress Hox gene expression in ES cells, is not dependent on its histone ubiquitination activity. We suggest that Ring1B-mediated chromatin compaction acts to directly limit transcription in vivo. Biological replicates: 3 independently grown, harvested,preplated, micrococcal nuclease digested and ChIP for H3K27me3. 5 Technical replicates.
2010-05-14 | E-GEOD-20213 | biostudies-arrayexpress
Project description:ChIP-seq for H3K27me3 and Ring1B was performed in WT mESCs and mESCs containing catalytically inactive Ring1B (I53A mutant). Cells expressing catalytically inactive Ring1B maintain the spatial distribution of Ring1B and H3K27me3 but at reduced levels. These findings support the notion that PRC2 recruitment is, in part, dependent on H2A ubiquitination (H2AK119ub).
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Project description:Polycomb repressive complex PRC1 is essential for gene regulation in numerous cell fate decisions. We show that RING1B (RING2, RNF2) and canonical PRC1 (cPRC1) genes are amplified and overexpressed in breast cancer (BC). Moreover, cPRC1 complexes functionally associate with genes regulated by cell type specific key transcription factors such as estrogen receptor (ER) in ER+ tumor cells and BRD4 in triple negative BC cells. cPRC1 is recruited to active enhancers in a manner independent of PRC2 and RING1B enzymatic activity. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of BC oncogenes but also by regulating chromatin accessibility for oncogenic transcription factors. RING1B recruitment, and thus PRC1 association, to active enhancers occurs in multiple cancers.
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Project description:ChIP-seq for H3K27me3 and Ring1B was performed in WT mESCs and mESCs containing catalytically inactive Ring1B (I53A mutant). Cells expressing catalytically inactive Ring1B maintain the spatial distribution of Ring1B and H3K27me3 but at reduced levels. These findings support the notion that PRC2 recruitment is, in part, dependent on H2A ubiquitination (H2AK119ub). Two biological replicates were performed for Ring1B and H3K27me3 ChIPs in WT and Ring1B I53A/I53A mouse ESCs. Input chromatin was sequenced for each replicate as a control for ChIP enrichment.
2015-09-20 | E-GEOD-69955 | biostudies-arrayexpress
Project description:We report the distribution of RING1B (one of Polycomb group factors) within the genome of mouse embryonic tissues. We prepared the chromatin from 11 dpc embryonic forebrain, midbrain, and forelimb buds and made chromatin precipitation with antibody against RING1B (mouse monoclonal antibody). High-throughput sequencing applied for the ChIP analysis revealed the differential distribution of RING1B protein among embryonic tissues.
2014-01-14 | GSE48464 | GEO
Project description:In addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ERbeta is a more desirable therapeutic target because ERalpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERbeta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ERbeta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ERbeta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ERbeta or ERalpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ERbeta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERbeta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERbeta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERbeta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERbeta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders. Keywords: estrogen receptor, gene regulation, TNF
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Project description:Comparison of the transcriptome of bone marrow derived macrophages infected with either metastasizing (M+, Lg13) or non-metastasizing (M-, Lg17) parasites after 24 hours of infection.
2011-01-03 | GSE21418 | GEO
Project description:This experiment was designed to determine the extent of gene misregulation in mESCs containing catalytically dead Ring1B in comparison to mESCs lacking Ring1B.
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