Research Papers:

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

Sayaka Funata, Keisuke Matsusaka, Ryota Yamanaka, Shogo Yamamoto, Atsushi Okabe, Masaki Fukuyo, Hiroyuki Aburatani, Masashi Fukayama and Atsushi Kaneda _

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Oncotarget. 2017; 8:55265-55279. https://doi.org/10.18632/oncotarget.19423

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Sayaka Funata1,2, Keisuke Matsusaka1, Ryota Yamanaka3, Shogo Yamamoto3, Atsushi Okabe1, Masaki Fukuyo1, Hiroyuki Aburatani3, Masashi Fukayama2 and Atsushi Kaneda1

1Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

2Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

3Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Correspondence to:

Atsushi Kaneda, email: [email protected]

Keywords: DNA methylation, Epstein-Barr virus, gastric cancer

Received: April 25, 2017     Accepted: July 11, 2017     Published: July 21, 2017


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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