Epstein-Barr virus infection induces genome-wide<i>de novo</i>DNA methylation in non-neoplastic gastric epithelial cells

Matsusaka, Keisuke; Funata, Sayaka; Fukuyo, Masaki; Seto, Yasuyuki; Aburatani, Hiroyuki; Fukayama, Masashi; Kaneda, Atsushi

doi:10.1002/path.4909

Cited by 42 publications

(58 citation statements)

References 14 publications

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“…In gastric cancer cells, EBV forms type I latency, where viral genome undergoes dense DNA methylation compared to other latencies, and the host genome shows extensively high-methylation epigenotype [ 4 ], named EBV-CIMP [ 6 ]. EBV infection itself was shown to establish this extensive DNA methylation in our previous study [ 4 , 7 ].…”

Section: Introductionmentioning

confidence: 84%

“…Some genes, named common marker genes, are commonly methylated in low-methylation, high-methylation/MSI+, and extensively high-methylation/EBV+ gastric cancer cases; MKN7, a low-methylation gastric cancer cell line, shows methylation in these genes, while GES1, a normal gastric epithelial cell immortalized with SV40, is not methylated in these genes. EBV infection was shown to cause genome-wide methylation and thus induce EBV-CIMP in both MKN7 and GES1 [ 4 , 7 ]. Here, we show that DNA methylation-induced genes in EBV-infected MKN7 were generally classified into “DNA methylation-sensitive” and “DNA methylation-resistant” depending on methylation status around the TSS, that histone modification was also dynamically altered with EBV infection, and that histone modification alteration occurred in a coordinated manner with DNA methylation alteration.…”

Section: Discussionmentioning

confidence: 99%

“…As the standpoint of the cause for aberrant DNA methylation in gastric cancer, EBV is demonstrated to induce de novo DNA methylation in host gastric epithelial cells during infection, which may be crucial for EBV-positive gastric carcinogenesis [ 4 , 7 ]. EBV is a γ-herpes virus establishing lifelong asymptomatic infection called “latency” in B-lymphocytes in almost all human populations.…”

Section: Introductionmentioning

confidence: 99%

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Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection

et al. 2017

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Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were “DNA methylation-sensitive” genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A. The other half were “DNA methylation-resistant” genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection

et al. 2017

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“…Matsusaka et al showed that when EBV was introduced into the EBV-negative/low-methylation epigenotype gastric cancer cell MKN7, DNA methylation was induced in the cells [ 42 ]. They recently described the observation of similar DNA methylation in non-neoplastic gastric epithelial cell line GES1 after EBV infection [ 43 ]. They concluded that DNA methylation could be attributed to EBV infection.…”

Section: Dna Hypermethylation In the Host Genomementioning

confidence: 99%

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer

Nishikawa

Iizasa

Yoshiyama

et al. 2017

IJMS

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The Epstein–Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.

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“…Although these functions of viral factors might partly contribute to tumorigenesis in EBV + malignancies, other molecular aberrations, eg genomic and epigenomic aberrations, in host cells need to be elucidated. We have previously reported that EBV + GC showed extensively high DNA methylation phenotype at gene promoter regions and abundant TSGs, eg p16 , are repressed by the aberrant promoter hypermethylation 13,14 . We also found that in vitro EBV infection in gastric epithelial cells introduces extensive DNA hypermethylation resembling the hypermethylation phenotype of clinical EBV + GC tissue samples.…”

Section: Introductionmentioning

confidence: 60%

Epstein‐Barr virus‐positive gastric cancer involves enhancer activation through activating transcription factor 3

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractEpstein-Barr virus (EBV) is associated with particular forms of gastric cancer (GC).We previously showed that EBV infection into gastric epithelial cells induced aberrant DNA hypermethylation in promoter regions and silencing of tumor suppressor genes. We here undertook integrated analyses of transcriptome and epigenome alteration during EBV infection in gastric cells, to investigate activation of enhancer regions and related transcription factors (TFs) that could contribute to tumorigenesis. Formaldehyde-assisted isolation of regulatory elements (FAIRE) sequencing (-seq) data revealed 19 992 open chromatin regions in putative H3K4me1 + H3K4me3 − enhancers in EBV-infected MKN7 cells (MKN7_EB), with 10 260 regions showing increase of H3K27ac. Motif analysis showed candidate TFs, eg activating transcription factor 3 (ATF3), to possibly bind to these activated enhancers. ATF3 was considerably upregulated in MKN7_EB due to EBV factors including EBV-determined nuclear antigen 1 (EBNA1), EBV-encoded RNA 1, and latent membrane protein 2A. Expression of mutant EBNA1 decreased copy number of the EBV genome, resulting in relative downregulation of ATF3 expression. Epstein-Barr virus was also infected into normal gastric epithelial cells, GES1, confirming upregulation of ATF3. Chromatin immunoprecipitation-seq analysis on ATF3 binding sites and RNA-seq analysis on ATF3 knocked-down MKN7_EB revealed 96 genes targeted by ATF3-activating enhancers, which are related with cancer hallmarks, eg evading growth suppressors. These 96 ATF3 target genes were significantly upregulated in MKN7_EB compared with MKN7 and significantly downregulated when ATF3 was knocked down in EBVpositive GC cells SNU719 and NCC24. Knockdown of ATF3 in EBV-infected MKN7, SNU719, and NCC24 cells all led to significant decrease of cellular growth through | 1819 ASAKAWA et Al.

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Epstein-Barr virus infection induces genome-widede novoDNA methylation in non-neoplastic gastric epithelial cells

Cited by 42 publications

References 14 publications

Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection

Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer

Epstein‐Barr virus‐positive gastric cancer involves enhancer activation through activating transcription factor 3

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