Post-infectious time-series DNA methylation analysis in gastric epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89269 | GEO | 2017/04/28
SECONDARY ACCESSION(S): PRJNA351217
REPOSITORIES: GEO
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Project description:Extensive DNA methylation in promoter regions is observed in gastric cancer with Epstein-barr virus (EBV) infection and EBV infection is the cause to induce this extensive hypermethylaiton phenotype in gastric epithelial cells. From transcriptome analysis, we found that TET2, one of the demethylase enzymes, was downregulated by EBV infection in gastric epithelial cell line MKN7. TET2 was overexpressed in a gastric epithelial cell line, GES1, to see its function and the hydroxymethylation, a byproduct of DNA demethylation, acquired genes by TET2 overexpression and methylation acquired genes by EBV infection were significantly overlapped. These suggested that hydroxymethylation by TET2 could function to keep unmethylated status of genes before EBV infection, and TET2 depression could contribute to methylation acquisition of these target genes after EBV infection.
2017-04-28 | GSE84897 | GEO
Project description:Aberrant promoter methylation is known to be deeply involved in human gastric carcinogenesis, while association of Epstein-Barr virus (EBV) to the aberrant methylation has not been fully clarified. We analyzed promoter methylation in clinical gastric cancer cases using illumina's Infinium beadarray, and hierarchical clustering analysis classified gastric cancer into three subgroups: low and high methylation epigenotypes in EBV-negative cases, and markedly higher methylation epigenotype that was completely matched to EBV-positive cases. Three epigenotypes were characterized by three groups of genes: genes methylated specifically in the EBV-positive epigenotype (EBV(+)-markers, e.g. CXXC4, TIMP2, PLXND1), genes methylated both in EBV-positive and high epigenotypes (High-markers, e.g. COL9A2, EYA1, ZNF365), and genes methylated all in EBV-positive, high and low epigenotypes of gastric cancer (Common-markers, e.g. AMPH, SORCS3, AJAP1). Polycomb repressive complex (PRC)-target genes in ES cells were significantly enriched in High- and Common-markers (P=2x10-15 and 2x10-34, respectively), but not in EBV(+)-markers (P=0.2), suggesting a different cause for EBV(+)-marker methylation. Recombinant EBV was infected to low epigenotype gastric cancer cell, MKN7. In all the three independently established clones, DNA methylation was induced in High- and EBV(+)-markers after 18 weeks, demonstrating that EBV-positive epigenotype should involve methylation of Common-, High-, and EBV(+)-markers simultaneously. The de novo methylated genes were overlapped well among the three clones, and the methylation caused gene repression. In summary, gastric cancer was classified into three DNA methylation epigenotypes, EBV-positive gastric cancer showed markedly high methylation epigenotype expanding to non-PRC target genes, and EBV infection per se could induce the EBV-positive epigenotype.
2012-01-04 | GSE31788 | GEO
Project description:Aberrant promoter methylation is known to be deeply involved in human gastric carcinogenesis, while association of Epstein-Barr virus (EBV) to the aberrant methylation has not been fully clarified. We analyzed promoter methylation in clinical gastric cancer cases using illumina's Infinium beadarray, and hierarchical clustering analysis classified gastric cancer into three subgroups: low and high methylation epigenotypes in EBV-negative cases, and markedly higher methylation epigenotype that was completely matched to EBV-positive cases. Three epigenotypes were characterized by three groups of genes: genes methylated specifically in the EBV-positive epigenotype (EBV(+)-markers, e.g. CXXC4, TIMP2, PLXND1), genes methylated both in EBV-positive and high epigenotypes (High-markers, e.g. COL9A2, EYA1, ZNF365), and genes methylated all in EBV-positive, high and low epigenotypes of gastric cancer (Common-markers, e.g. AMPH, SORCS3, AJAP1). Polycomb repressive complex (PRC)-target genes in ES cells were significantly enriched in High- and Common-markers (P=2x10-15 and 2x10-34, respectively), but not in EBV(+)-markers (P=0.2), suggesting a different cause for EBV(+)-marker methylation. Recombinant EBV was infected to low epigenotype gastric cancer cell, MKN7. In all the three independently established clones, DNA methylation was induced in High- and EBV(+)-markers after 18 weeks, demonstrating that EBV-positive epigenotype should involve methylation of Common-, High-, and EBV(+)-markers simultaneously. The de novo methylated genes were overlapped well among the three clones, and the methylation caused gene repression. In summary, gastric cancer was classified into three DNA methylation epigenotypes, EBV-positive gastric cancer showed markedly high methylation epigenotype expanding to non-PRC target genes, and EBV infection per se could induce the EBV-positive epigenotype.
2012-01-04 | GSE31787 | GEO
Project description:The CpG island methylator phenotype (CIMP) is associated with prognosis and drug sensitivity in multiple cancer types. In gastric cancer, the CIMP is closely associated with Epstein-Barr virus (EBV) infection and AT-rich interactive domain 1A (ARID1A) mutations, a component of the SWI/SNF chromatin remodeling complex. However, the involvement of SWI/SNF defects in CIMP induction has been unclear. In this study, we demonstrate a causal role of ARID1A loss-of-function in CIMP induction. Mutations of SWI/SNF components, especially ARID1A, was associated with the CIMP, as well as EBV infection, in gastric cancers, and also in uterine endometrial and colorectal cancers, which are not affected by EBV infection. Genome-wide DNA methylation analysis showed that ARID1A knockout (KO) in cultured 293FT cells and gastric epithelial cells, GES1, induced aberrant DNA methylation of a substantial number of CpG sites. DNA methylation was induced at genomic regions with high levels of pre-existing histone H3 lysine 27 trimethylation (H3K27me3) and those with acquired H3K27me3 by ARID1A KO. These results showed that the ARID1A mutation induced aberrant DNA methylation, and this is likely to be one of the potential mechanisms of CIMP induction. (See GSE188293 for data of GES1 with ARID1A KO.)
2022-10-31 | GSE165239 | GEO
Project description:Gastric cancer is one of the most common cancers worldwide. Epstein-Barr virus-associated gastric cancer accounts for approximately 10% of all gastric cancers. EBV expresses its own proteins and miRNAs (BART miRNAs) and regulates host gene expression. In this study, we examined the effect of EBV infection on host mRNA expression. Differential gene expression was analyzed between EBV-negative human gastric cancer cell line AGS and EBV-positive human gastric cancer cell line AGS-EBV.
2019-10-14 | GSE135644 | GEO
Project description:We analysed epigenetic alterations by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis. We performed ChIP-seq on H3K4me3, H3K4me1, H3K27ac, H3K27me3 and H3K9me3 using gastric epithelial cells with or without EBV infection. We showed that repressive marks were redistributed after EBV infection, resulting in aberrant enhancer activation and repression. Enhancer dysfunction leads to activation of pathway related to cancer hallmarks (e.g. resisting cell death, disrupting cellular energetics, activation invasion, evading growth suppressors, sustaining proliferative signaling, angiogenesis and tumor promoting inflammation) and inactivation of tumour suppressive pathway. Dysregulation of cancer-related genes during in vitro EBV infection were also observed in EBV+ gastric cancer patients. Our analysis showed that EBV-infection associated epigenetic alteration may contribute to tumorigenesis through enhancer activation and repression.
2017-08-21 | GSE97838 | GEO
Project description:Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced ERK1/2 and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126 or autophagy initiation inhibitor 3-MA suppressed C6-Cer-induced EBV lytic replication. In contrast, the autophagosome-lysosome fusion inhibitor chloroquine induced BZLF1 expression. Transfection with siCREB reduced ERK1/2 phosphorylation and C6-Cer-induced BZLF1 expression. On the other hand, siJUN transfection did not affect BZLF1 expression. Our results show that increased endogenous ceramide and glycosyl ceramide (GlyCer) following C6-Cer treatment induce EBV lytic replication in gastric cancer cells via ERK1/2 and CREB phosphorylation and autophagosome accumulation.
2023-12-20 | MTBLS7649 | MetaboLights
Project description:To understand epigenic dysregulation of host and viral genes upon EBV infection in human gastric cancer, genome wide transcripts by RNAseq were undertaken for total RNAs of 3 EBVnGC, their isogenic cell lines converted by in vitro EBV-infection and 3 EBV-naturally infected GC cell lines.
2014-09-01 | GSE60873 | GEO
Project description:Gastric cancer, a leading cause of cancer related deaths, is a heterogeneous disease, with little consensus on molecular subclasses and their clinical relevance. We describe four molecular subtypes linked with distinct patterns of molecular alterations, disease progression and prognosis viz. a) Microsatellite Instable: hypermutated intestinal subtype tumors occurring in antrum, best overall prognosis, lower frequency of recurrence (22%), with liver metastasis in 23% of recurred cases b) Mesenchymal-like: diffuse tumors with worst prognosis, a tendency to occur at an earlier age and highest recurrence (63%) with peritoneal seeding in 64% of recurred cases, low frequency of molecular alterations c) TP53-inactive with TP53 loss, presence of focal amplifications and chromosomal instability d) TP53-active marked by EBV infection and PIK3CA mutations. The key molecular mechanisms and associated survival patterns are validated in multiple independent cohorts, to provide a consistent and unified framework for further preclinical and clinical research. ACRG Gastric cohort: microarray profiles from 300 gastric tumors from gastric cancer patients.
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