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Genome-wide maps of H3K27me3 and H3K27ac in cells treated with HDAC inhibition, EZH2 inhibition, or combined HDAC/EZH2 inhibition

ABSTRACT: Genome-wide maps of H3K27me3 and H3K27ac in cells treated with HDAC inhibition, EZH2 inhibition, or combined HDAC/EZH2 inhibition

PROVIDER: PRJNA631783 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11773150.fastq.gz	Fastqsanger.gz
	SRR11773151.fastq.gz	Fastqsanger.gz
	SRR11773152.fastq.gz	Fastqsanger.gz
	SRR11773153.fastq.gz	Fastqsanger.gz
	SRR11773154.fastq.gz	Fastqsanger.gz

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Genome-wide maps of H3K27me3 and H3K27ac in cells treated with HDAC inhibition, EZH2 inhibition, or combined HDAC/EZH2 inhibition

Project description:Investigation of the mechanism by which combined EZH2 and HDAC inhibition kills PC3 prostate cancer cells. Next-generation sequencing was used to identify changes in genome localization of HDAC targets (H3K27ac) and EZH2 targets (H3K27me3) upon treatment with each inhibitor alone or in combination.

2020-05-12 | GSE150336 | GEO

Chromatin Accessibility Analysis Reveals Distinct Functions for HDAC and EZH2 Activities in Early Regeneration

Project description:Xenopus tropicalis tadpoles have the capability to scarlessly regenerate appendages including the limb and tail. Following injury, complex genetic processes must be activated and inactivated with high spatial and temporal resolution to result in a properly patterned appendage. Functional studies have established that histone modifying enzymes that act to close chromatin are required for regeneration, but the genomic regions sensitive to these activities are not established. Here we show that early inhibition of HDAC or Ezh2 activity results in incomplete regeneration. To identify the impact that each of these perturbations has on chromatin accessibility, we applied an assay for transposase accessible chromatin (ATAC-seq) to HDAC or Ezh2 inhibited regenerating tadpoles. We find that neither perturbation results in a global increase in chromatin accessibility, but that both inhibitors have targeted effects on chromatin accessibility and gene expression. Upon HDAC inhibition, promoter regions and regulatory regions neighboring genes associated with neuronal regeneration are precociously accessible, whereas following EZH2 inhibition we find gene bodies and regulatory regions associated with regulation of the immune response and apoptosis are preferentially accessible. Together this suggests distinct roles for EZH2 activity and HDAC activity in appendage regeneration.

2022-05-01 | GSE175662 | GEO

Expression data in PC3 prostate cancer cells treated with DMSO, HDAC inhibitor, EZH2 inhibitor, or combined HDAC and EZH2 inhibitors.

Project description:Expression data in PC3 prostate cancer cells treated with DMSO, HDAC inhibitor, EZH2 inhibitor, or combined HDAC and EZH2 inhibitors.

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HDAC inhibition, dopamine and long-term fear inhibition

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An Ezh2 and Ezh1 dual inhibitor, UNC1999, re-shapes the landscape of H3K27me3 versus H3K27ac in MLL-AF9-transformed murine leukemia

Project description:Ezh2 and EZH1 are histone H3 lysine 27 (H3K27)-specific methyltransferases. Their hyperactive mutations and overexpression were found in cancer including various hematological malignancies. UNC1999 is a highly selective inhibitor for both enzymes. It suppresses H3K27 tri- and di-methylation globally and inhibits growth of MLL-rearranged acute leukemia. Here we performed ChIP-Seq to profile how UNC1999 affects distribution of H3K27me3 and its antagonizing H3K27ac in MLL-AF9-immortalized leukemia cells. We also performed ChIP-seq of SUZ12, an essential common cofactor of EZH2 and EZH1 following compound treatments. We treated MLL-AF9 transformed murine leukemia cells with DMSO, UNC1999 or UNC2400 (an inactive analog compound of UNC1999). Cells were then collected and used for ChIP-Sequencing of Input, H3K27me3, SUZ12, and H3K27ac.

2014-10-30 | E-GEOD-62437 | biostudies-arrayexpress

CUT&RUN profiling of histone H3K27ac and H3K27me3 localization after pharmacological inhibition of EZH2 and BET proteins

Project description:NUT carcinoma (NC), an aggressive carcinoma, is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and when fused to NUT forms very large super-enhancers, termed megadomains. Targeting BRD4-NUT with BET bromodomain inhibitors (BETi) are a promising treatment, but limited as monotherapy. To identify additional dependencies in NC, we performed a genetic rescue screen in NC cells depleted of BRD4-NUT and identified EZH2 as a top correlated hit. Indeed, inhibition of EZH2 using the clinical compound, tazemetostat (taz), potently blocked growth of NC cells, and when combined with BETi was highly synergistic. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on megadomain-associated genes. CDKN2A was identified as the only amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-CAS9 screen. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort.

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Regulation of Histone Acetylation by SUMOylation Through TFAP2C Binding to the Chromatin and Recruitment of HDAC Complex

Project description:Enhancers are fundamental to gene regulation. Post-translational modifications by the small ubiquitin-like modifiers (SUMO) modify chromatin regulation enzymes, including histone acetylases and deacetylases. However, it remains unclear whether SUMOylation regulates enhancer marks, acetylation at the 27th lysine residue of the histone H3 protein (H3K27Ac). We hypothesize that SUMOylation regulates H3K27Ac. To test this hypothesis, we performed genome-wide ChIP-seq analyses. We discovered that knockdown (KD) of the SUMO activating enzyme catalytic subunit UBA2 reduced H3K27Ac at most enhancers. Bioinformatic analysis revealed that TFAP2C-binding sites are enriched in enhancers whose H3K27Ac was reduced by UBA2 KD. ChIP-seq analysis in combination with molecular biological methods showed that TFAP2C binding to enhancers increased upon UBA2 KD or inhibition of SUMOylation by a small molecule SUMOylation inhibitor. However, this is not due to the SUMOylation of TFAP2C itself. Proteomics analysis of TFAP2C interactome on the chromatin identified histone deacetylation (HDAC) machinery. TFAP2C KD reduced HDAC binding to chromatin and increased H3K27Ac marks at enhancer regions, suggesting that TFAP2C is involved in recruiting HDAC. Taken together, our findings provide important insights into regulation of enhancer marks by SUMOylation.

2024-04-13 | PXD045644 | Pride

Genome-wide Profiling of H3K27ac binding in human cancer cell lines

Project description:Upregulation of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and its associated histone H3 lysine 27 (H3K27) trimethylation frequently occur in human cancer, yet both preclinical and clinical evidence suggested the very limited benefit of EZH2-targeted therapies. This study investigated the underlying mechanisms from a perspective of EZH2 inhibition-caused histone modification crosstalk. A mass spectrometry approach enabled us discovering the alteration of global histone modifications responding to EZH2 inhibition. Feedback upregulation of H3K27 acetylation (H3K27ac) level is closely associated with limited drug response to EZH2 inhibition across multiple cancer types. H3K27ac alteration caused transcriptional activation of oncoproteins confers drug resistant to EZH2 inhibition. Here we used ChIP-Seq analysis to identify the alteration of genome-wide H3K27ac bingding sites with EZH2 inhibitor treatment in human cancer cell lines.

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Targeting Glioma Stem Cells through Combined BMI1 and EZH2 Inhibition [RNA-seq]

Project description:Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these features are associated with distinct transcriptional programs, with vascular regions showing a Proneural profile and hypoxic regions a Mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas Mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress. Using both genetic and pharmacologic inhibition, we found that Proneural GSCs are selectively sensitive to EZH2 disruption, whereas Mesenchymal GSCs are sensitive to BMI1 inhibition. Given that glioblastomas contain both Proneural and Mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be necessary to overcome resistance to therapies caused by intratumoral heterogeneity.

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Project description:Mutations or aberrant upregulation of the histone methyltransferase EZH2 occur frequently in human cancers yet EZH2-targeted therapies have only shown very limited clinical benefits in hematological malignancies. We report here that upon EZH2 inhibition, MLL1 interacts with p300/CBP complex that directs H3K27me loss to gain of H3K27ac modification. This histone modification crosstalk leads to transcriptional reprogramming that restricts the therapeutic response to EZH2 inhibition. Concurrent inhibition of H3K27 methylation and acetylation results in transcriptional repression and growth dependency on the MAPK signaling pathway in a large cancer subset. In pre-clinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors or a triple-combination including MAPK inhibition display robust efficacy with tolerable toxicity, in particular in liver and pancreatic cancers. Our results suggest an attractive precision treatment and patient stratification strategy for EZH2-aberrant tumors on the basis of intrinsic MLL1 expression and feedback MAPK activation.

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