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Transcriptional response to zebularine and mitomycin C (MMC) in wild type and ATR deficient Arabidopsis thaliana plants

ABSTRACT: Zebularine is a non-methylable cytidine analog that is used in epigenetic and cancer research. Its application has been shown to activate several transcriptionally silenced genetic elements; however, extent of this activation and other effects on the transcriptome are unknown. Here, we show that zebularine treatment induces preferentially genes associated with DNA damage repair response and this activation is strongly ATR-dependent. The set of up- and down-regulated genes after 24 h zebularine treatment is almost fully contained in the set of genes with changed transcription in response to 24 h MMC treatment. We identified only few genes that were up-regulated in common by longer (5 days) zebularine treatment and loss of epigenetic control in ddm1 mutant. Our results suggest that zebularine does not induce global activation of targets of transcriptional gene silencing and indicate previously unanticipated DNA damaging effects associated with zebularine-treatment.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE63355 | GEO | 2014/11/18

SECONDARY ACCESSION(S): PRJNA267558

REPOSITORIES: GEO

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Transcriptional response to zebularine and mitomycin C (MMC) in wild type and ATR deficient Arabidopsis thaliana plants

Project description:Zebularine is a non-methylable cytidine analog that is used in epigenetic and cancer research. Its application has been shown to activate several transcriptionally silenced genetic elements; however, extent of this activation and other effects on the transcriptome are unknown. Here, we show that zebularine treatment induces preferentially genes associated with DNA damage repair response and this activation is strongly ATR-dependent. The set of up- and down-regulated genes after 24 h zebularine treatment is almost fully contained in the set of genes with changed transcription in response to 24 h MMC treatment. We identified only few genes that were up-regulated in common by longer (5 days) zebularine treatment and loss of epigenetic control in ddm1 mutant. Our results suggest that zebularine does not induce global activation of targets of transcriptional gene silencing and indicate previously unanticipated DNA damaging effects associated with zebularine-treatment. Examination of transcriptional changes in response to mock, 24 h and 5 days 20 uM zebularine and 24 h 10 uM MMC treatment in Arabidopsis wild-type and/or atr-2.

2014-11-18 | E-GEOD-63355 | biostudies-arrayexpress

Characterization of A. baumannii Mitomycin C (MMC) response

Project description:Transcriptional profiling of A. baumannii ATCC 17978 comparing treated-MMC cultures with non-MMC treated cultures

2013-11-14 | GSE44735 | GEO

Characterization of A. baumannii Mitomycin C (MMC) response

Project description:Transcriptional profiling of A. baumannii ATCC 17978 comparing treated-MMC cultures with non-MMC treated cultures Two-condition experiment A. baumannii 17978 MMC+ vs A. baumannii 17978 MMC-. Biological replicates:3, Technical replicates:2

2013-11-14 | E-GEOD-44735 | biostudies-arrayexpress

ChIP-Seq with anti-FLAG antibodies to determine binding of LexA-3xFLAG to DNA in Streptomyces venezuelae treated with Mitomycin C (MMC) overnight

Project description:LexA is a transcriptional repressor for genes requiring expression primarily during SOS response in response to stress such as that caused by DNA alkylating agent Mitomycin C (MMC). LexA undergoes self-cleavage under stress conditions thereby lifting the repression on genes whose expression is required for stress response. In our experiment LexA binding sites in the genome were determined in untreated and MMC treated (overnight, 14h) cultures using a LexA-3xFLAG strain and anti-FLAG monoclonal antibodies. Wild type Streptomyces venezuelae (unFLAGged LexA) cultures, with and without MMC treatment were used as negative controls.

2022-07-06 | E-MTAB-11603 | biostudies-arrayexpress

DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.

Project description:Hepatocellular carcinoma is one of the most common cancers in world wide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine [1-(β-ᴅ-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. Here, we demonstrated that zebularine exhibited antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis. Zebularine treatment down-regulated CDK2 and phosphorylation of retinoblastoma protein (RB), and up-regulated p21WAF/CIP1 and p53. We also found that zebularine treatment up-regulated phosphorylation of p44/42 MAPK. These results suggest that p44/42 MAPK pathway play a role in zebularine induced cell cycle arrest by regulating activity of p21WAF/CIP1 and Rb. Furthermore, we found that zebularine induced apoptosis. Although proapoptotic protein Bax levels were not affected, antiapoptotic protein Bcl-2 level was down-regulated with zebularine treatment. The data in the present study suggest that the action of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results provide a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma.

2013-12-01 | GSE42490 | GEO

Gene expression profile of bladder cancer cell lines treated with Mitomycin C

Project description:Mitomycin C (MMC) is the gold standard treatment for non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate in bladder cancer cell lines (T24, 5637, TCC-SUP and CLS-439) the transcriptomic response to MMC treatment. We used Gene Set Enrichment Analysis (GSEA) to identify biological processes and pathways modulated by MMC treatment.

2021-01-02 | GSE151505 | GEO

Genome-wide analysis of E.coli response to mitomycin (MMC) treatment in wild type and recN mutant

Project description:We report the role of recN in the induction of the sos response Examination of gene profiling at two time points after addition of mitomycin (MMC) at 10Âµg/ml

2016-04-01 | E-GEOD-74882 | biostudies-arrayexpress

DNA Methyltransferase Inhibitor Zebularine Induces Human Cholangiocarcinoma Cell Death through Alteration of DNA Methylation Status

Project description:Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms “hemophilic cell adhesion”, “regulation of transcription, DNAdependent” and “Wnt signaling pathway” were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased β-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation-independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer.

2015-03-24 | GSE60446 | GEO

DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.

2013-12-01 | E-GEOD-42490 | biostudies-arrayexpress

Effect of zebularine on primary human liver cancer cell lines

Project description:Transcriptomic changes in human liver cancer cell lines caused by the demethylating drug zebularine. Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in mice. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome.

2011-07-31 | GSE23991 | GEO

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