Epigenome analysis of dnmt target sites [3ABDKO cell line]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79648 | GEO | 2016/04/08
SECONDARY ACCESSION(S): PRJNA316600
REPOSITORIES: GEO
Similar Datasets
Project description:Genome wide DNA methylation profiling of target sites of dnmt3b isoforms in HCT derivative cell line 3BKO followed by 5-Aza-CdR treatment. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450,000 CpGs
2016-04-08 | GSE68342 | GEO
Project description:Genome wide DNA methylation profiling of target sites of dnmt3b isoforms in HCT derivative cell line DKO8. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450,000 CpGs
2016-04-08 | GSE62670 | GEO
Project description:Genomide DNA methylation profiling of HCT116 cells after PBS, 5-Aza-CdR, vitamin C and combination treatment. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 480,000 CpGs in HCT116 cells.
2016-08-30 | GSE77036 | GEO
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with cases increasing dramatically in the USA. Developing more effective targeted therapies for HCC is an urgent need. The FDA-approved DNA methyltransferase inhibitors (DNMTis) 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2’-deoxycytidine (5-aza-CdR, Decitabine) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, the clinical efficacies of DNMTis are still limited, in part due to an “epigenetic switch” mechanism, in which a large group of genes demethylated by DNMTi treatment remain silenced by Polycomb Repressive Complex 2 (PRC2) occupancy. Overexpression of PRC2 subunits, especially EZH2, is correlated with poor patient survivor in HCC. In this study, we tested the combination of 5-Aza-CdR and the EZH2 inhibitor (EZH2i) GSK-126 in human HCC cell lines (SNU398, HepG2, and SNU475) on DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all cell lines showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently silenced genes. The increased number of up-regulated genes, including tumor suppressors, were correlated with prolonged anti-proliferation effects and nucleosome accessibility but negatively correlated with gene promoter DNA methylation. Detailed epigenome analyses reveal a mechanistic rationale in which the combination treatment of 5-aza-CdR with an EZH2 inhibitor (EZH2i) activates demethylated promoters that are repressed by PRC2 occupancy. Furthermore, about 13.6% to 31% of genes down-regulated by DNA methylation in primary HCC tumors can be reactivated through this combination treatment scheme in vitro. Finally, combination treatment also exacerbates viral mimicry activation as well as leukocyte, lymphocyte and T cell mediated immunity, while most those genes or pathways were downregulated in over 50% of primary HCC tumors in TCGA dataset. Conclusion: we have linked the anti-tumor effects of DNMTi and EZH2i combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.
2022-10-19 | GSE202559 | GEO
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with cases increasing dramatically in the USA. Developing more effective targeted therapies for HCC is an urgent need. The FDA-approved DNA methyltransferase inhibitors (DNMTis) 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2’-deoxycytidine (5-aza-CdR, Decitabine) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, the clinical efficacies of DNMTis are still limited, in part due to an “epigenetic switch” mechanism, in which a large group of genes demethylated by DNMTi treatment remain silenced by Polycomb Repressive Complex 2 (PRC2) occupancy. Overexpression of PRC2 subunits, especially EZH2, is correlated with poor patient survivor in HCC. In this study, we tested the combination of 5-Aza-CdR and the EZH2 inhibitor (EZH2i) GSK-126 in human HCC cell lines (SNU398, HepG2, and SNU475) on DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all cell lines showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently silenced genes. The increased number of up-regulated genes, including tumor suppressors, were correlated with prolonged anti-proliferation effects and nucleosome accessibility but negatively correlated with gene promoter DNA methylation. Detailed epigenome analyses reveal a mechanistic rationale in which the combination treatment of 5-aza-CdR with an EZH2 inhibitor (EZH2i) activates demethylated promoters that are repressed by PRC2 occupancy. Furthermore, about 13.6% to 31% of genes down-regulated by DNA methylation in primary HCC tumors can be reactivated through this combination treatment scheme in vitro. Finally, combination treatment also exacerbates viral mimicry activation as well as leukocyte, lymphocyte and T cell mediated immunity, while most those genes or pathways were downregulated in over 50% of primary HCC tumors in TCGA dataset. Conclusion: we have linked the anti-tumor effects of DNMTi and EZH2i combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.
2022-10-19 | GSE202560 | GEO
Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic M-bM-^@M-^\imprintM-bM-^@M-^] of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. Cytosine methylation profile of 4 different samples of HEK 293T treated with 5-aza-CdR
2015-02-13 | E-GEOD-62592 | biostudies-arrayexpress
Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic M-bM-^@M-^\imprintM-bM-^@M-^] of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. mRNA profile of 5 different samples of HEK 293T cells treated with 5-aza-CdR
2015-02-13 | E-GEOD-62591 | biostudies-arrayexpress
Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic M-bM-^@M-^\imprintM-bM-^@M-^] of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. Examination of RNAPII Ser5(P) localization by ChIP-seq in HEK 293T cell after treatment with 5-aza-CdR.
2015-02-13 | E-GEOD-62695 | biostudies-arrayexpress
Project description:Background:Aberrant DNA methylation that silences tumor suppressor genes occurs frequently in patients with acute myeloid leukemia (AML). Treatment of AML patients with the inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) can induce complete remissions, but most patients will relapse. The clinical efficacy of 5-AZA-CdR may be influenced by its limited capacity to activate tumor suppressor genes silenced by methylation of lysine 27 histone H3 (H3K27) by EZH2. In order to overcome this limitation, we investigated previously the antileukemic action of 5-AZA-CdR in combination with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep) on HL-60 AML cells. We observed a remarkable synergistic interaction against these AML cells for this combination. In this study, we investigated in more depth the action of 5-AZA-CdR plus DZNep on gene expression in AML cells using RNA sequence analysis Result:In a colony assay, 5-AZA-CdR in combination with DZNep exhibited also a potent synergy against another human AML cell line: AML-3. The induction of apoptosis in HL-60 and AML3 leukemic cells by 5-AZA-CdR plus DZNep was also synergistic. RNA sequence analysis on HL-60 leukemic cells showed that the combination of 5-AZA-CdR plus DZNep increased the expression of thousands of genes. The genes upregulated by this combination included genes related to differentiation, development, senescence, apoptosis, and tumor suppressor function. Many of the genes activated by 5-AZA-CdR plus DZNep have the potential to suppress leukemogenesis. Conclusion: The activation of many genes by the combination of 5-AZA-CdR plus DZNep correlates with its synergistic antileukemic action. The block in differentiation is one of the hallmarks of AML.The activation of many genes that program differentiation and development by this combination of epigenetic agents has the potential to reverse this block. The reversal of these two epigenetic genesilencing mechanisms by 5-AZA-CdR plus DZNep merits clinical investigation in patients with AML
2017-02-01 | GSE94344 | GEO
Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2’-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic “imprint” of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation.
2015-02-13 | GSE62592 | GEO