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The DNMT1 inhibitor GSK-3484862 mediates global demethylation in murine embryonic stem cells

ABSTRACT: The DNMT1 inhibitor GSK-3484862 mediates global demethylation in murine embryonic stem cells

PROVIDER: PRJNA763210 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15898019_1.fastq.gz	Fastqsanger.gz
	SRR15898019_2.fastq.gz	Fastqsanger.gz
	SRR15898020_1.fastq.gz	Fastqsanger.gz
	SRR15898020_2.fastq.gz	Fastqsanger.gz
	SRR15898021_1.fastq.gz	Fastqsanger.gz

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The DNMT1 inhibitor GSK-3484862 mediates global demethylation in murine embryonic stem cells

Project description:We generated WGBS datasets from mESCs treated with the novel drug GSK-3484862 attained from two different commercial sources or the conventional DNMT1 inhitibitor 5-azacytidine. To assess efficacy, datasets were generated from mESCs treated with GSK-3484862 at two concentrations and after treatment for 6 days and 14 days each. Additionally, for comparison purposes, we generated WGBS datasets from Dnmt1/3a/3b deficient mESCs which have very low levels of DNA methylation and WT mESCs treated with DMSO which retain high levels of DNA methylation.

2021-12-14 | GSE184116 | GEO

The DNMT1 inhibitor GSK-3484862 mediates global demethylation in murine embryonic stem cells.

Project description:BackgroundDNA methylation plays an important role in regulating gene expression in mammals. The covalent DNMT1 inhibitors 5-azacytidine and decitabine are widely used in research to reduce DNA methylation levels, but they impart severe cytotoxicity which limits their demethylation capability and confounds interpretation of experiments. Recently, a non-covalent inhibitor of DNMT1 called GSK-3484862 was developed by GlaxoSmithKline. We sought to determine whether GSK-3484862 can induce demethylation more effectively than 5-azanucleosides. Murine embryonic stem cells (mESCs) are an ideal cell type in which to conduct such experiments, as they have a high degree of DNA methylation but tolerate dramatic methylation loss.ResultsWe determined the cytotoxicity and optimal concentration of GSK-3484862 by treating wild-type (WT) or Dnmt1/3a/3b triple knockout (TKO) mESC with different concentrations of the compound, which was obtained from two commercial sources. Concentrations of 10 µM or below were readily tolerated for 14 days of culture. Known DNA methylation targets such as germline genes and GLN-family transposons were upregulated within 2 days of the start of GSK-3484862 treatment. By contrast, 5-azacytidine and decitabine induced weaker upregulation of methylated genes and extensive cell death. Whole-genome bisulfite sequencing showed that treatment with GSK-3484862 induced dramatic DNA methylation loss, with global CpG methylation levels falling from near 70% in WT mESC to less than 18% after 6 days of treatment with GSK-3484862. The treated cells showed a methylation level and pattern similar to that observed in Dnmt1-deficient mESCs.ConclusionsGSK-3484862 mediates striking demethylation in mESCs with minimal non-specific toxicity.

| S-EPMC8672470 | biostudies-literature

PHF8 mediates histone demethylation events in cell cycle progression

Project description:This SuperSeries is composed of the following subset Series: GSE22477: PHF8 mediates histone demethylation events in cell cycle progression [expression] GSE22478: PHF8 mediates histone demethylation events in cell cycle progression [ChIP-Seq] Refer to individual Series

2010-08-31 | E-GEOD-22400 | biostudies-arrayexpress

RNA-seq of DNMT1 inhibitor treated AML cell lines

Project description:Genome wide demethylation by DNMT1 inhibitors GSK3685032 results in up-regulation of epigenetically-silenced genes.

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Epic methylation arrays of DNMT1 inhibitor treated AML cell lines

Project description:Genome wide demethylation by DNMT1 inhibitor GSK3685032 results in up-regulation of epigenetically-silenced genes

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Expression array of DNMT1 inhibitor treated AML cell lines

Project description:Genome wide demethylation by DNMT1 inhibitor GSK3484862 results in up-regulation of epigenetically-silenced genes. Differential expression was perfomed for each cell line following DNMT1 inhibitor or vehicle treatment. Differentially epressed gene lists were submitted to gene set enrichment analysis (GSEA) to identify consistently changed pathways.

2022-12-31 | GSE134716 | GEO

MethylationEPIC array of DNMT1 inhibitor treated AML cell lines - part II

Project description:Genome wide demethylation by DNMT1 inhibitor GSK3484862 results in up-regulation of epigenetically-silenced genes. Methylation was assayed for each cell line following DNMT1 inhibitor or vehicle treatment. Global methylation distributions were compared between treated and untreated samples.

2021-06-30 | GSE135206 | GEO

Expression array of DNMT1 inhibitor treated 3 AML cell lines

Project description:Genome wide demethylation by DNMT1 inhibitor GSK3484862 results in up-regulation of epigenetically-silenced genes Differential expression was perfomed for each cell line following DNMT1 inhibitor or vehicle treatment. Differentially epressed gene lists were submitted to gene set enrichment analysis (GSEA) to identify consistently changed pathways.

2022-12-31 | GSE134742 | GEO

A mutant DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ?RFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-?RFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer. DNA samples from HBEC3 cells transfected with vector control and HBEC3 cells with full-length and RFTS-deleted DNMT1 were assessed for genome-wide methylation using the microarray-based high resolution HpaII tiny fragment enriched by ligation-mediated PCR (HELP) assay.

2014-09-30 | E-GEOD-57829 | biostudies-arrayexpress

GSK-3 inhibitor treatment effect on MLL leukemia cell

Project description:Human leukemia cell line RS4.11 was treated with GSK-3 inhibitor SB216763 for 20 hours. Gene expression profiling was performed to analyze genes affected by GSK-3 inhibition. Human leukemia cell line RS4.11 was grown in vitro and treated with 10 uM GSK-3 inhibitor SB216763 or solvent DMSO for 20 hours. Total RNA was extracted and microarray analysis was performed. Two controls and three inhibitor treatment samples were analyzed.

2010-05-27 | E-GEOD-19736 | biostudies-arrayexpress

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