Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma

Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Manjie Xing, Xuewen Ong, Takayuki Hoshii, Genki Usui, Motoaki Seki, Yasunobu Mano, Bahityar Rahmutulla, Teru Kanda, Takayoshi Suzuki, Sun Young Rha, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


Epstein–Barr virus (EBV) is associated with several human malignancies including 8–10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human–viral interactions with non-integrated EBV episomes. EBV infection in vitro suffices to remodel chromatin topology and function at EBV-interacting host genomic loci, converting H3K9me3+ heterochromatin to H3K4me1+/H3K27ac+ bivalency and unleashing latent enhancers to engage and activate nearby GC-related genes (for example TGFBR2 and MZT1). Higher-order epigenotypes of EBV-positive GC thus signify a novel oncogenic paradigm whereby non-integrative viral genomes can directly alter host epigenetic landscapes (‘enhancer infestation’), facilitating proto-oncogene activation and tumorigenesis.

Original languageEnglish
Pages (from-to)919-930
Number of pages12
JournalNature Genetics
Issue number9
Publication statusPublished - 2020 Sept 1

Bibliographical note

Funding Information:
We thank A. Saraya, E. Ikeda and H. Maruyama for technical assistance. We thank S. Tsutsumi for support with analysis of the Hi-C data. This work was supported by P-CREATE 19cm0106510h0004 (A.K.) and Practical Research for Innovative Cancer Control 19ck0106263h0003 (A.K.) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (KAKENHI) 19H03726 (A.K.) and 19K16101 (A.O.) from the Japan Society for the Promotion of Science, a Specific Research grant from Takeda Science Foundation (A.K.), Global and Prominent Research grant 2018-Y9 (A.K.) from Chiba University, Duke-NUS Medical School grant RL2016-080 (P.T.), National Medical Research Council grants NMRC/STaR/0026/2015 (P.T.) and OF-LCG18May-0023 (P.T.), and the Cancer Science Institute of Singapore, National University of Singapore, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

  • Genetics


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