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

doi:10.1038/s41588-020-0665-7

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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	919-930
Number of pages	12
Journal	Nature Genetics
Volume	52
Issue number	9
DOIs	https://doi.org/10.1038/s41588-020-0665-7
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-020-0665-7

Cite this

Okabe, A., Huang, K. K., Matsusaka, K., Fukuyo, M., Xing, M., Ong, X., Hoshii, T., Usui, G., Seki, M., Mano, Y., Rahmutulla, B., Kanda, T., Suzuki, T., Rha, S. Y., Ushiku, T., Fukayama, M., Tan, P., & Kaneda, A. (2020). Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma. Nature Genetics, 52(9), 919-930. https://doi.org/10.1038/s41588-020-0665-7

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

abstract = "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 ({\textquoteleft}enhancer infestation{\textquoteright}), facilitating proto-oncogene activation and tumorigenesis.",

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

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: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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Okabe, A, Huang, KK, Matsusaka, K, Fukuyo, M, Xing, M, Ong, X, Hoshii, T, Usui, G, Seki, M, Mano, Y, Rahmutulla, B, Kanda, T, Suzuki, T, Rha, SY, Ushiku, T, Fukayama, M, Tan, P & Kaneda, A 2020, 'Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma', Nature Genetics, vol. 52, no. 9, pp. 919-930. https://doi.org/10.1038/s41588-020-0665-7

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T1 - Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma

AU - Okabe, Atsushi

AU - Huang, Kie Kyon

AU - Matsusaka, Keisuke

AU - Fukuyo, Masaki

AU - Xing, Manjie

AU - Ong, Xuewen

AU - Hoshii, Takayuki

AU - Usui, Genki

AU - Seki, Motoaki

AU - Mano, Yasunobu

AU - Rahmutulla, Bahityar

AU - Kanda, Teru

AU - Suzuki, Takayoshi

AU - Rha, Sun Young

AU - Ushiku, Tetsuo

AU - Fukayama, Masashi

AU - Tan, Patrick

AU - Kaneda, Atsushi

N1 - 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.

PY - 2020/9/1

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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