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Oncogenic Ras signaling disrupts PRC2 via EED downregulation to drive oncogenic reprogramming and niche remodeling in squamous cell carcinoma [mouse CUT & RUN]

ABSTRACT: Squamous cell carcinoma (SCC) is a common epithelial malignancy, yet its epigenetic underpinnings remain poorly defined. Here, we identify the Polycomb Repressive Complex 2 (PRC2) as a key epigenetic barrier of SCC tumorigenesis. Despite high EZH2 levels, the PRC2-dependent H3K27me3 is depleted in human and murine SCCs, indicating complex destabilization rather than enzymatic failure. Mechanistically, oncogenic Ras signaling downregulates the PRC2 scaffolding subunit EED, disrupting PRC2 and H3K27me3 and activating oncogenic loci. Depletion of Eed in epidermal progenitors disrupts the proliferation–differentiation balance and, upon carcinogen exposure, drives invasive SCC. Single-cell RNA-seq of Eed-deficient tumors reveals an expansion of tumor-specific keratinocytes and a remodeled pro-tumorigenic microenvironment. Notably, reintroducing EED in SCC cells restores PRC2 integrity and H3K27me3 levels, suppressing tumor growth and mitigating the pro-tumorigenic niche. Our findings establish PRC2 as an essential epigenetic gatekeeper in SCC and suggest restoring PRC2-mediated repression may offer a novel therapeutic strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE305084 | GEO | 2026/06/13

REPOSITORIES: GEO

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Oncogenic Ras signaling disrupts PRC2 via EED downregulation to drive oncogenic reprogramming and niche remodeling in squamous cell carcinoma [mouse RNA-Seq]

Project description:Squamous cell carcinoma (SCC) is a common epithelial malignancy, yet its epigenetic underpinnings remain poorly defined. Here, we identify the Polycomb Repressive Complex 2 (PRC2) as a key epigenetic barrier of SCC tumorigenesis. Despite high EZH2 levels, the PRC2-dependent H3K27me3 is depleted in human and murine SCCs, indicating complex destabilization rather than enzymatic failure. Mechanistically, oncogenic Ras signaling downregulates the PRC2 scaffolding subunit EED, disrupting PRC2 and H3K27me3 and activating oncogenic loci. Depletion of Eed in epidermal progenitors disrupts the proliferation–differentiation balance and, upon carcinogen exposure, drives invasive SCC. Single-cell RNA-seq of Eed-deficient tumors reveals an expansion of tumor-specific keratinocytes and a remodeled pro-tumorigenic microenvironment. Notably, reintroducing EED in SCC cells restores PRC2 integrity and H3K27me3 levels, suppressing tumor growth and mitigating the pro-tumorigenic niche. Our findings establish PRC2 as an essential epigenetic gatekeeper in SCC and suggest restoring PRC2-mediated repression may offer a novel therapeutic strategy.

2026-06-13 | GSE305085 | GEO

Oncogenic Ras signaling disrupts PRC2 via EED downregulation to drive oncogenic reprogramming and niche remodeling in squamous cell carcinoma [human CUT & RUN]

2026-06-13 | GSE305083 | GEO

The Central Role of EED in the Orchestration of Polycomb Group Complexes

Project description:Polycomb Repressive Complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency, and neoplastic progression1-3. Here we show that the Polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of the PRC1 complex. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1 mediated H2A ubiquitin E3 ligase activity. Taken together, we uncover the integral role of EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2. EED, uH2A, RING1A, RING1B, BMI1 and H3K27Me3 ChIP-seq in EED stable knockdown and control Scramble DU145 prostate cancer cell line

2014-01-23 | E-GEOD-42566 | biostudies-arrayexpress

EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

Project description:In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PCR2 writing of H3K27me3 is mechanistically required for gene silencing. Here we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (Embryonic Ectoderm Development) inactivation in the postnatal heart (Eed CKO ) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in Eed CKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized Eed CKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

2017-04-14 | GSE73771 | GEO

The Central Role of EED in the Orchestration of Polycomb Group Complexes

2014-01-23 | GSE42566 | GEO

Polycomb protein EED is required for selective silencing of pluripotency genes upon ESC differentiation

Project description:Eed (embryonic ectoderm development) is a core component of the Polycomb Repressive Complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) can act as a signal for PRC1 recruitment in the process of gene silencing and chromatin condensation. Previous studies with Eed KO ESCs revealed a failure to down-regulate a limited list of pluripotency factors in differentiating ESCs. Our aim was to analyze the consequences of Eed KO for ESC differentiation. To this end we first analyzed ESC differentiation in the absence of Eed and employed in silico data to assess pluripotency gene expression and H3K27me3 patterns. We linked these data to expression analyses of wildtype and Eed KO ESCs. We observed that in wildtype ESCs a subset of pluripotency genes including Oct4, Nanog, Sox2 and Oct4 target genes progressively gain H3K27me3 during differentiation. These genes remain expressed in differentiating Eed KO ESCs. This suggests that the deregulation of a limited set of pluripotency factors impedes ESC differentiation. Global analyses of H3K27me3 and Oct4 ChIP-seq data indicate that in ESCs the binding of Oct4 to promoter regions is not a general predictor for PRC2-mediated silencing during differentiation. However, motif analyses suggest a binding of Oct4 together with Sox2 and Nanog at promoters of genes that are PRC2-dependently silenced during differentiation. In summary, our data further characterize Eed function in ESCs by showing that Eed/PRC2 is essential for the onset of ESC differentiation. RNAs obtained from undifferentiated (d0) wild type and Eed KO ESCs and from day 3 (d3) and day 7 (d7) respective Ebs were subjected to Affymetrix Mouse Gene 1.0 ST Array. 24 samples in total.

2014-08-28 | E-GEOD-49305 | biostudies-arrayexpress

PRC2 molecule EED is a target of epigenetic therapy of neuroblastoma

Project description:Epigenetic modification by polycomb repressive complex (PRC) molecules appears to have a role in tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic Ectoderm Development (EED) is a member of PRC2 complex and binds the H3K27me3 mark deposited by EZH2, via propagation on adjacent nucleosomes. Here we studied the molecular roles of EED in MYCN-amplified neuroblastoma cells by using EED-knocked down shRNAs, EED-knocked out sgRNAs, and EED small molecule inhibitor EED226. EED suppression profoundly inhibited the NB cell proliferation and flat-and soft agar colony formation. Transcriptome analysis by microarray of the EED-KD NB cells indicated the de-repression of the cell cycle regulated and differentiation-related genes; GSEA analysis results suggested that cell cycle repressed gene sets were strongly upregulated. Further, epigenetic treatment by the combination of EED inhibitor EED226 and HDAC inhibitor valproic acid effectively suppressed NB cell proliferation and colony formation. The combinatory epigenetic treatment up-regulated the cell cycle regulation- and differentiation-related genes.

2022-09-03 | GSE183369 | GEO

Polycomb protein EED is required for selective silencing of pluripotency genes upon ESC differentiation

2014-08-28 | GSE49305 | GEO

EED in the Polycomb Repressive Complex 2 Epigenetically Regulates Responses in Lipopolysaccharide Tolerized Macrophages

Project description:To avoid exaggerated inflammation and injury, host cells adapt to become hypo-responsive or “tolerance” in response to successive exposure to stimuli. Such tolerized response is a part of innate immune memory which is mainly regulated via epigenetics changes and metabolic reprograming. Polycomb repressive complex 2 (PRC2) mediates the transcriptional repression by catalyzing histone H3 lysine 27 trimethylation (H3K27me3) but little is known about the roles of PRC2 in tolerant macrophages. We examined the impact of PRC2 components, EED and Ezh2, on lipopolysaccharide (LPS)-induced tolerant macrophages. In Eed KO macrophages, not only the significant reduction in H3K27me3, but also the augmentation of an active histone mark, H3K27Ac. Upon EED deletion but not Ezh2, macrophages exhibited attenuated pro-inflammatory cytokines productions (TNF-α and IL-6) in LPS-tolerant cells. In addition, LPS tolerant Eed KO macrophages exhibited low glycolytic activity rather than its littermate wild-type control. RNA-Seq analyses revealed that most of differentially expressed genes are involved in oxidative phosphorylation and TGF-β signaling. Alteration of H3K27me3 and H3K27ac in the regulatory regions of some of these genes were validated. These results indicated that PRC2 via EED epigenetically suppresses these genes in response to LPS re-exposure and lacking PRC2 activity results in hypo-responsive to LPS re-stimulation. Therefore, we provide strong evidences that PRC2 via EED mediates LPS tolerance in macrophages by epigenetically suppressing proinflammatory responses with the link to dysregulated metabolic pathway.

2023-06-20 | GSE234655 | GEO

Transcriptional repression by non-canonical EED stimulation of histone deacetylase activity is required for heart maturation independently of H3K27me3 [RNA-seq for EED and HDAC rescue]

Project description:Through H3K27me3 and H3K27ac ChIP-seq and RNA-seq data in wile-tpye (WT) and EED-knockout (CKO) mouse cardiomyocytes, we unexpectedly uncovered a novel mechanism of PRC2-mediated gene repression. EED inactivation in the postnatal heart (EEDCKO) caused progressive, lethal dilated cardiomyopathy, with upregulation of components of the slow-twitch muscle gene program. Surprisingly, upregulation of these genes was not associated with their loss of H3K27me3, but rather with their gain of H3K27 acetylation (H3K27ac), an activating histone mark. Moreover, re-expression of EED in juvenile hearts rescued heart function and normalized H3K27ac, but not H3K27me3.

2017-04-14 | GSE89585 | GEO

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