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Super-enhancer analysis of EBV-associated T/NK lymphoma

Research Project

Project/Area Number 21K15448
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 49060:Virology-related
Research InstitutionNagoya University

Principal Investigator

Sato Yoshitaka  名古屋大学, 医学系研究科, 准教授 (40754940)

Project Period (FY) 2021-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordsEpstein-Barrウイルス / ゲノム高次構造 / ウイルス遺伝子発現 / スーパーエンハンサー / ゲノム立体構造 / T/NK細胞リンパ腫 / ゲノム相互作用 / CAEBV / T/NK腫瘍
Outline of Research at the Start

Epstein-Barrウイルス(EBV)は、B細胞を自然宿主とする普遍的なウイルスであるが、時にT細胞およびNK細胞にも感染し、節外性NK/T細胞リン パ腫・鼻型、急速進行性NK細胞白血病や慢性活動性EBV感染症などの血液腫瘍の原因となる。これらのEBV 関連T/NK細胞腫瘍は日本をはじめとした東アジアで報告が多く、予後不良で有効な治療法は未だ存在しない。
本研究では、細胞を特徴付ける転写プロファイルと密接な関係をもつスーパーエンハンサーを解析し、EBV関連T/NK細胞腫瘍に特異的なスーパーエンハンサーを同定する。そして、予後不良なEBV関連T/NK細胞腫瘍の新たな治療法の開発を目指す。

Outline of Final Research Achievements

Epstein-Barr virus (EBV) persists in human cells as episomes. EBV episomes are chromatinized and their 3D conformation varies greatly in cells expressing different latency genes. we compared the EBV episome intragenomic interactions in different cancer cell lines expressing three different types of EBV latency genes using a new method, HiChIP. H3K27ac HiChIPs were done in 4 T/NK lymphoma cell lines and 2 primary effusion lymphoma cell lines, together with published data from cell line expressing type III latency genes. We found that in type II latency infected cells, the episome looping patterns were similar to cells expressing type III latency genes. Similar to previous reports using a different method to compare the EBV 3D genome looping using captured Hi-C, more restricted type I latency infected cells had much less loopings. These data suggested that looping is a way for EBV to regulate its oncogene expression in various EBV associated cancer cells.

Academic Significance and Societal Importance of the Research Achievements

ヒト腫瘍ウイルス Epstein-Barrウイルス(EBV)が陽性であるT/NK細胞性腫瘍(EBV関連T/NK細胞腫瘍)は日本をはじめとした東アジアで報告が多く、予後不良で有効な治療法は未だ存在しない。本研究では、ウイルスゲノムが感染細胞内で高次構造をとり、ウイルスゲノム内でのゲノム間相互作用の構造の違いにより、ウイルス遺伝子発現が制御されていることが明らかとなった。ゲノム編集によりEBVゲノムに構造変化を加えると、EBV遺伝子発現も変化し、ゲノム高次構造が治療標的となる可能性が示唆された。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (18 results)

All 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 6 results,  Invited: 3 results)

  • [Int'l Joint Research] ハーバード大学/ノースカロライナ大学/デューク大学(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] ハーバード大学/ノースカロライナ大学(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] The Epstein-Barr Virus Enhancer Interaction Landscapes in Virus-Associated Cancer Cell Lines2022

    • Author(s)
      Ding Weiyue、Wang Chong、Narita Yohei、Wang Hongbo、Leong Merrin Man Long、Huang Alvin、Liao Yifei、Liu Xuefeng、Okuno Yusuke、Kimura Hiroshi、Gewurz Benjamin、Teng Mingxian、Jin Shuilin、Sato Yoshitaka、Zhao Bo
    • Journal Title

      Journal of Virology

      Volume: 96 Issue: 18

    • DOI

      10.1128/jvi.00739-22

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome-wide CRISPR screen for HSV-1 host factors reveals PAPSS1 contributes to heparan sulfate synthesis2022

    • Author(s)
      Suzuki Takeshi、Sato Yoshitaka、Okuno Yusuke、Goshima Fumi、Mikami Tadahisa、Umeda Miki、Murata Takayuki、Watanabe Takahiro、Watashi Koichi、Wakita Takaji、Kitagawa Hiroshi、Kimura Hiroshi
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 694-694

    • DOI

      10.1038/s42003-022-03581-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producing cells facilitates de novo infection2022

    • Author(s)
      Sato Yoshitaka、Yaguchi Masahiro、Okuno Yusuke、Ishimaru Hanako、Sagou Ken、Ozaki Somi、Suzuki Takeshi、Inagaki Tomoki、Umeda Miki、Watanabe Takahiro、Fujimuro Masahiro、Murata Takayuki、Kimura Hiroshi
    • Journal Title

      Cell Communication and Signaling

      Volume: 20 Issue: 1 Pages: 95-95

    • DOI

      10.1186/s12964-022-00902-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] INDUCTION OF IMPDH2 AND NUCLEOLAR HYPERTROPHY ARE REQUIRED FOR GROWTH TRANSFORMATION OF RESTING B CELLS BY EBV2022

    • Author(s)
      Takayuki Murata, Atsuko Sugimoto, Takahiro Watanabe, Yusuke Yanagi, Kazuhiro Matsuoka, Yusuke Okuno, Yoshitaka Sato, Teru Kanda, Yasumasa Iwatani, Hiroshi Kimura
    • Organizer
      The 20th Biennial Conference International Association for Research on Epstein-Barr Virus and Associated Diseases
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] シングルセルシーケンスを用いたEBウイルス関連血球貪食性リンパ組織球症の病態解析2022

    • Author(s)
      鈴木高子, 佐藤好隆, 鳥居ゆか, 福田悠人, 春田一憲, 山口慎, 奥野友介, 濱麻人, 木村宏, 伊藤嘉規, 川田潤一
    • Organizer
      第54回日本小児感染症学会総会・学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] EBV溶解感染遺伝子BNRF1はアポトーシス阻害により腫瘍形成を促進する2022

    • Author(s)
      佐合健, 佐藤好隆, 奥野友介, 渡辺崇広, 木村宏
    • Organizer
      第69回日本ウイルス学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 内因性微粒子が駆動するウイルス関連疾患の理解2022

    • Author(s)
      佐藤好隆
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] EBV溶解感染遺伝子BNRF1の欠損は腫瘍形成能を著しく低下させる2022

    • Author(s)
      佐合健、佐藤好隆、奥野友介、渡辺崇広、木村宏
    • Organizer
      第35回ヘルペスウイルス研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] A genome-wide CRISPR screen reveals the importance of genes related to heparan sulfate biosynthesis and the requirement of PAPSS1 for HSV-1 infection and binding2021

    • Author(s)
      Takeshi Suzuki, Yoshitaka Sato, Yusuke Okuno, Takayuki Murata, Takahiro Watanabe, Hiroshi Kimura
    • Organizer
      The 45th Annual International Herpesvirus Workshop (IHW2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] The abortive lytic phase occurred prior to latency establishment during EBV primary infection to B-cells2021

    • Author(s)
      Yoshitaka Sato, Tomoki Inagaki, Yusuka Okuno, Takahiro Watanabe, Takayuki Murata and Hiroshi Kimura
    • Organizer
      The 45th Annual International Herpesvirus Workshop (IHW2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Exosomes containing Epstein-Barr virus tegument proteins are released from the infected cells and support de novo infection to target cells2021

    • Author(s)
      Yoshitaka Sato, Masahiro Yaguchi, Yusuke Okuno, Hanako Ishimaru, Takahiro Watanabe, Masahiro Fujimuro, Takayuki Murata, Hiroshi Kimura
    • Organizer
      The 19th International Symposium on EBV and associated diseases (EBV2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Epstein-Barr virus carrying structural variations in hematological and epithelial cell malignancies2021

    • Author(s)
      Yusuke Okuno, Takayuki Murata, Yoshitaka Sato, Yoshinori Ito, Akihisa Sawada, Koichi Ohshima, Seiichi Kato, Masato Nakaguro, Akira Satou, Hiroshi Kimura
    • Organizer
      The 19th International Symposium on EBV and associated diseases (EBV2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Genomic landscape in CAEBV cell lines2021

    • Author(s)
      Yohei Narita, Weiyue Ding, Chong Wang, Merrin Man Long Leong, Hongbo Wang, Minxiang Teng, Hiroshi Kimura, Yoshitaka Sato, Bo Zhao
    • Organizer
      The 19th International Symposium on EBV and associated diseases (EBV2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Exosomal transfer of Epstein-Barr virus tegument protein BGLF2 and its contribution to the infection2021

    • Author(s)
      佐藤好隆
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 慢性活動性EBV病患者由来細胞で認めるウイルスゲノムの高次構造解析2021

    • Author(s)
      佐藤好隆, 成田洋平, Minxiang Teng, 木村宏, Bo Zhao
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 新型および旧型コロナウイルスのウイルス学的特徴と今後の課題2021

    • Author(s)
      佐藤好隆
    • Organizer
      第34回日本動物細胞工学会2021年度大会
    • Related Report
      2021 Research-status Report
    • Invited

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Published: 2021-04-28   Modified: 2024-01-30  

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