Abstract
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.
Highlights
Cancer development and progression occur through accumulation of genetic and epigenetic disruptions [1, 2]
Our data show that orchestrated epigenetic alterations are important in gene regulation during Epstein-Barr virus (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
These findings suggested that unmethylated CpG sites were unevenly maintained or protected under DNA methylation induction during EBV infection
Summary
Cancer development and progression occur through accumulation of genetic and epigenetic disruptions [1, 2]. Many tumor suppressor genes were de novo methylated and inactivated in cancer cells, which contributes to carcinogenesis [2, 3]. These aberrant DNA methylations seemed to occur in a nonrandom manner, and many types of cancer are classified into several epigenotypes based on the degree of DNA methylation. Gastric cancer is classified into at least three DNA methylation phenotypes: low-methylation, highmethylation, and extensively high-methylation epigenotypes [4]. These methylation epigenotypes reflect molecular subtypes such as microsatellite-instable (MSI) gastric cancer or Epstein-Barr virus (EBV)-associated gastric cancer [5, 6]
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