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Epigenomic profiling of Non-small-cell Lung Cancer (NSCLC) cells with or without Eed

ABSTRACT: Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung cancer (NSCLC) progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances Kras-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell autonomous epithelial-to-mesenchymal transition (EMT) program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt-signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE61190 | GEO | 2016/01/15

SECONDARY ACCESSION(S): PRJNA260490

REPOSITORIES: GEO

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Epigenomic profiling of Non-small-cell Lung Cancer (NSCLC) cells with or without Eed

Project description:Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung cancer (NSCLC) progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances Kras-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell autonomous epithelial-to-mesenchymal transition (EMT) program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt-signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application. We generated ChIP-seq from primary Kras;p53 (KP) cells in culture with and without Eed (KPE) and from KP primary tumors generated by injection of NSCLC into the tail vein. Mice were sacrificed on the onset of shortness of breath. We generated genome-wide expression profiles (RNA-seq) and Nuclease Accessibility (NA)-seq in primary KP and KPE tumor cells. NA-seq was also performed in A549 cells.

2016-01-15 | E-GEOD-61190 | 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

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.

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Bulk RNA-seq of Colonic Epithelia from EED and EED/Satb2 Double Knockout Mice

Project description:To understand the polycomb repressive complex 2 (PRC2) function, we genetically deleted EED, which inactivated PRC2, in adult intestine and colon using (VillinCreER-T2;EEDf/f).

2021-10-05 | GSE180013 | 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

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

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

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

Acetylation of EED by CBP/P300 Regulates the Targeting of PRC2 and is Required for mESC Differentiation [ChIP-seq]

Project description:Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyzes the methylation of lysine 27 on histone H3 (H3K27me1/2/3). This complex maintains the gene expression profiles in different cell types and plays an essential role in normal organismal development. The mechanisms by which PRC2 targets specific chromatin regions remain unclear. To address this question, we focused on the post-translational modifications (PTMs) of PRC2 subunits. Here we show EED, a core component of PRC2, is acetylated by acetyltransferase CBP/P300 at lysine 19 (K19). The acetylation of EED at K19 (EED-K19ac) reduces the binding affinity between PRC2 and native nucleosomes, causing PRC2 to leave its chromatin targets in vivo. Genome-wide location analysis (ChIP-seq) reveals that K19-acetylated EED preferentially accumulates at highly transcribed genes with low EZH2 and H3K27me3 levels. Using CRISPR/Cas9 technology, we generated mouse embryonic stem cells (mESCs) carrying non-acetylated EED mimic (EED-K19R) and showed acetylation of EED at K19 is necessary for mESC differentiation. In summary, our study reveals a novel mechanism that allows intracellular signalling pathways to regulate cellular differentiation and cell fate decisions by controlling the genomic targeting of PRC2 through acetylating EED.

2023-09-30 | GSE160211 | GEO

Acetylation of EED by CBP/P300 Regulates the Targeting of PRC2 and is Required for mESC Differentiation [RNA-seq]

2023-09-30 | GSE160210 | GEO