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Elucidation of mRNA dysregulation in hepatocellular carcinoma using a novel mRNA methylome method

Research Project

Project/Area Number 23K21431
Project/Area Number (Other) 21H02894 (2021-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2021-2023)
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Nagae Genta  東京大学, 先端科学技術研究センター, 特任准教授 (10587348)

Co-Investigator(Kenkyū-buntansha) 緑川 泰  国立研究開発法人国立精神・神経医療研究センター, 病院 総合外科部, 部長 (10292905)
上田 宏生  東京大学, 先端科学技術研究センター, 特任講師 (70821916)
Project Period (FY) 2024-04-01 – 2025-03-31
Project Status Completed (Fiscal Year 2024)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2024: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2021: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywords肝癌 / RNA修飾 / 網羅的解析 / 網羅的分析
Outline of Research at the Start

継続課題のため、記入しない。

Outline of Final Research Achievements

In this project, we established a novel detection method that combines comprehensiveness, high accuracy, and high resolution through mathematical optimization using deep learning based on quantitative measurement data of mRNA methylation obtained by biochemical and physicochemical methods. By applying this detection system to RNA samples extracted from liver cancer cells, we clarified mRNA metabolism and regulation mechanisms and abnormalities occurring in cancer cells in terms of both transcriptional regulation and post-transcriptional modification.
We have improved the accuracy of the high-resolution modification identification method using direct RNA sequencing of m6A modification regions in liver cancer cell lines, and verified the accuracy of the method using control samples with IVT-amplified RNA synthesized using the modified bases as material, and confirmed an accuracy of over 80%.

Academic Significance and Societal Importance of the Research Achievements

RNA修飾そのものは古くから知られていたが、近年になってその生命現象における機能的役割が次々と明らかになってきた。一方で、現状においても個々の修飾分子に限られた研究が多く、網羅的検出法の解析精度も十分でないことから、制御システムとしての本質的な理解には至っていない。本研究の開発目標であるmRNA修飾の包括的検出法は、こうした状況を飛躍的に前進させることが期待され、また、がん細胞の分子生物学的異常の理解に新たな側面を加えるとともに、新規薬剤標的の探索をも期待される。

Report

(5 results)
  • 2024 Annual Research Report   Final Research Report ( PDF )
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (51 results)

All 2025 2024 2023 2022 2021 2020

All Journal Article (25 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 18 results,  Open Access: 16 results) Presentation (26 results) (of which Int'l Joint Research: 12 results,  Invited: 17 results)

  • [Journal Article] m6ATM: a deep learning framework for demystifying the m6A epitranscriptome with Nanopore long-read RNA-seq data2024

    • Author(s)
      Yu B, Nagae G, Midorikawa Y, Tatsuno K, Dasgupta B, Aburatani H, Ueda H
    • Journal Title

      Briefings in Bioinformatics

      Volume: 25 Issue: 6 Pages: 6-6

    • DOI

      10.1093/bib/bbae529

    • Related Report
      2024 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes2024

    • Author(s)
      Marumo T, Yoshida N, Inoue N, Yamanouchi M, Ubara Y, Urakami S, Fujii T, Takazawa Y, Ohashi K, Kawarazaki W, Nishimoto M, Ayuzawa N, Hirohama D, Nagae G, Fujimoto M, Arai E, Kanai Y, Hoshino J, Fujita T
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 327 Issue: 3 Pages: F397-F411

    • DOI

      10.1152/ajprenal.00124.2024

    • Related Report
      2024 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Integrated genomic/epigenomic analysis stratifies subtypes of clear cell ovarian carcinoma, highlighting their cellular origin2024

    • Author(s)
      Nishijima A, Oda K, Hasegawa K, Koso T, Asada K, Ikeda Y, Taguchi A, Maeda D, Nagae G, Tsuji S, Tatsuno K, Uehara Y, Kurosaki A, Sato S, Tanikawa M, Sone K, Mori M, Ikemura M, Fujiwara K, Ushiku T, Osuga Y, Aburatani H
    • Journal Title

      Scientific Reports

      Volume: 14 Issue: 1 Pages: 18797-18797

    • DOI

      10.1038/s41598-024-69796-4

    • Related Report
      2024 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Region‐specific DNA hydroxymethylation along the malignant progression of IDH‐mutant gliomas2024

    • Author(s)
      Hana T, Mukasa A, Nomura M, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Tanaka S, Nejo T, Kitagawa Y, Yamazawa E, Takahashi S, Koike T, Kushihara Y, Takami H, Takayanagi S, Aburatani H, Saito N
    • Journal Title

      Cancer Science

      Volume: 115 Issue: 5 Pages: 1706-1717

    • DOI

      10.1111/cas.16127

    • Related Report
      2024 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma2024

    • Author(s)
      Roehrig A, Hirsch TZ, Pire A, Morcrette G, Gupta B, Marcaillou C, Imbeaud S, Chardot C, Gonzales E, Jacquemin E, Sekiguchi M, Takita J, Nagae G, Hiyama E, Guerin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugieres L, Fresneau B, Zucman-Rossi J, Letouze E
    • Journal Title

      Nature Communications

      Volume: 15 Issue: 1 Pages: 3031-3031

    • DOI

      10.1038/s41467-024-47280-x

    • Related Report
      2024 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutational signature, cancer driver genes mutations and transcriptomic subgroups predict hepatoblastoma survival2024

    • Author(s)
      Pire A, Hirsch TZ, Morcrette G, Imbeaud S, Gupta B, Pilet J, Cornet M, Fabre M, Guettier C, Branchereau S, Brugieres L, Guerin F, Laithier V, Coze C, Nagae G, Hiyama E, Laurent-Puig P, Rebouissou S, Sarnacki S, Chardot C, Capito C, Faure-Conter C, Aerts I, Taque S, Fresneau B, Zucman-Rossi J
    • Journal Title

      European Journal of Cancer

      Volume: 200 Pages: 113583-113583

    • DOI

      10.1016/j.ejca.2024.113583

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation2024

    • Author(s)
      Neyazi S, Yamazawa E, Hack K, Tanaka S, Nagae G, Kresbach C, Umeda T, Eckhardt A, Tatsuno K, Pohl L, Hana T, Bockmayr M, Kim P, Dorostkar MM, Takami T, …, Ichimura K, Rutkowski S, Aburatani H, Saito N, Schller U.
    • Journal Title

      Acta Neuropathologica

      Volume: 147 Issue: 1 Pages: 22-22

    • DOI

      10.1007/s00401-023-02668-9

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] エピゲノム解析2024

    • Author(s)
      永江玄太
    • Journal Title

      がんゲノムペディア-77のキーワードで理解するゲノム医療とゲノム研究

      Volume: - Pages: 104-107

    • Related Report
      2023 Annual Research Report
  • [Journal Article] RNA Oncological Therapeutics: Intracellular Hairpin RNA Assembly Enables MicroRNA-Triggered Anticancer Functionality2023

    • Author(s)
      Morihiro, K.; Morita, S.; Harada, N.; Baba, M.; Yum, J.; Naito, M.; Miyata, K.; Nagae, G.; Okamoto, A.
    • Journal Title

      J. Am. Chem. Soc.

      Volume: 146 Issue: 2 Pages: 1346-1355

    • DOI

      10.1021/jacs.3c09524

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of viral genome with altered immune microenvironment during tumour progression of <scp>Epstein‐Barr virus</scp> ‐associated gastric carcinoma2023

    • Author(s)
      Kondo Atsushi、Shinozaki‐Ushiku Aya、Rokutan Hirofumi、Kunita Akiko、Ikemura Masako、Yamashita Hiroharu、Seto Yasuyuki、Nagae Genta、Tatsuno Kenji、Aburatani Hiroyuki、Koinuma Daizo、Ushiku Tetsuo
    • Journal Title

      The Journal of Pathology

      Volume: - Issue: 2 Pages: 124-136

    • DOI

      10.1002/path.6067

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiancestry genomic and transcriptomic analysis of gastric cancer2023

    • Author(s)
      Totoki Y, Saito-Adachi M, Shiraishi Y, Komura D, Nakamura H, Suzuki A, Tatsuno K, Rokutan H, Hama N, Yamamoto S, Ono H, Arai Y, Hosoda F, Katoh H, et al.
    • Journal Title

      Nature Genetics

      Volume: 55 Issue: 4 Pages: 581-594

    • DOI

      10.1038/s41588-023-01333-x

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 総論:疾患の病態解明に向けた統合オミックス解析2023

    • Author(s)
      永江玄太
    • Journal Title

      遺伝子医学

      Volume: 45 Pages: 1-7

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism2022

    • Author(s)
      Watanabe K, Kimura S, Seki M, Isobe T, Kubota Y, Sekiguchi M, Sato-Otsubo A, Hiwatari M, Kato M, Oka A, Koh K, Sato Y, Tanaka H, Miyano S, Kawai T, Hata K, Ueno H, Nannya Y, Suzuki H, Yoshida K, Fujii Y, Nagae G, Aburatani H, Ogawa S, Takita J.
    • Journal Title

      Oncogene

      Volume: 41 Issue: 46 Pages: 4994-5007

    • DOI

      10.1038/s41388-022-02489-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia2022

    • Author(s)
      Tomoya Isobe, Masatoshi Takagi, Aiko Sato-Otsubo, et al. (57人中28番目)
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 4501-4501

    • DOI

      10.1038/s41467-022-32266-4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 小児肝芽腫発症に関与する分化制御因子2022

    • Author(s)
      永江玄太
    • Journal Title

      生化学

      Volume: 94(3) Pages: 438-442

    • Related Report
      2022 Annual Research Report
  • [Journal Article] ヒトゲノム研究におけるマイクロアレイ解析(CGH・SNP・メチル化など)2022

    • Author(s)
      永江玄太
    • Journal Title

      病理と臨床 40(臨増)【がんゲノム医療時代の分子腫瘍学】

      Volume: - Pages: 057-063

    • Related Report
      2022 Annual Research Report
  • [Journal Article] 泌尿器科領域におけるシングルセル解析の可能性2022

    • Author(s)
      永江玄太
    • Journal Title

      泌尿器科

      Volume: 15(4) Pages: 465-471

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Genome-wide analysis of DNA methylation identifies the apoptosis-related gene UQCRH as a tumor suppressor in renal cancer2022

    • Author(s)
      Kosuke Miyakuni, Jun Nishida, Daizo Koinuma, Genta Nagae, Hiroyuki Aburatani, Kohei Miyazono, Shogo Ehata
    • Journal Title

      Molecular Oncology

      Volume: 16 Issue: 3 Pages: 732-749

    • DOI

      10.1002/1878-0261.13040

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic and epigenetic basis of hepatoblastoma diversity.2021

    • Author(s)
      Nagae G, Yamamoto S, Fujita M, Fujita T, Nonaka A, Umeda T, Fukuda S, Tatsuno K, Maejima K, Hayashi A, Kurihara S, Kojima M, Hishiki T, Watanabe K, Ida K, Yano M, Hiyama Y, Tanaka Y, Inoue T, Ueda H, Nakagawa H, Aburatani H, Hiyama E.
    • Journal Title

      Nat Commun.

      Volume: 12 Issue: 1 Pages: 5423-5423

    • DOI

      10.1038/s41467-021-25430-9

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Base-Resolution Analysis of 5-Hydroxymethylcytidine by Selective Oxidation and Reverse Transcription Arrest2021

    • Author(s)
      Koyama, K.; Hayashi, G.; Ueda, H.; Ota, S.; Nagae, G.; Aburatani, H.; Okamoto, A.
    • Journal Title

      Org. Biomol. Chem.

      Volume: 19 Issue: 29 Pages: 6478-6486

    • DOI

      10.1039/d1ob00995h

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular classification and diagnostics of upper urinary tract urothelial carcinoma2021

    • Author(s)
      藤井陽一、佐藤悠佑、鈴木啓道、川合剛人、森川鉄平、白石友一、中川徹、久米春喜、小川誠司他
    • Journal Title

      Cancer Cell

      Volume: 39 Issue: 6 Pages: 793-809

    • DOI

      10.1016/j.ccell.2021.05.008

    • NAID

      120007089270

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.2021

    • Author(s)
      Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
    • Journal Title

      Cancer Sci.

      Volume: 112 Issue: 7 Pages: 2855-2869

    • DOI

      10.1111/cas.14897

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] direct RNA sequenceとRNA修飾の情報解析2021

    • Author(s)
      上田 宏生
    • Journal Title

      実験医学別冊 ロングリードWET&DRY解析ガイド

      Volume: - Pages: 202-212

    • Related Report
      2021 Annual Research Report
  • [Journal Article] ナノポアシーケンサーを用いた RNA 修飾の解析2021

    • Author(s)
      山崎 洋人、上田 宏生
    • Journal Title

      細胞(特集 エピトランスクリプトミクス)

      Volume: 53(14) Pages: 896-899

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Discovering A-to-I RNA Editing Through Chemical Methodology “ICE-seq”2020

    • Author(s)
      Sakurai, M., Okada, S., Ueda, H., and Yang, Y.
    • Journal Title

      Methods in Molecular Biology

      Volume: 2181 Pages: 113-148

    • DOI

      10.1007/978-1-0716-0787-9_8

    • ISBN
      9781071607862, 9781071607879
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] Liquid Biopsyのための標的探索と診断実装2025

    • Author(s)
      永江玄太
    • Organizer
      Liquid Biopsy研究会
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] Zonationに基づいたMASH進展機序の解明2025

    • Author(s)
      永江玄太
    • Organizer
      第3回PMTI研究会
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] 個別化医療におけるエピゲノム異常の意義と標的可能性について2025

    • Author(s)
      永江玄太
    • Organizer
      エピジェネティックメディスン研究会
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] Comprehensive methylation analysis of pediatric liver cancer using SRS and LRS2025

    • Author(s)
      Genta Nagae
    • Organizer
      SIOPEL annual meeting,
    • Related Report
      2024 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん細胞のメチル化異常を用いた病態理解と臨床応用2024

    • Author(s)
      永江玄太
    • Organizer
      藤田医科大学 腫瘍医学研究センターセミナー
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] がん検診への実装を目指すメチル化パネルアッセイシステムの開発2024

    • Author(s)
      永江玄太
    • Organizer
      第63回日本消化器がん検診学会総会
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] 疾患病態解明に向けた先進的ゲノム機能解析2024

    • Author(s)
      永江玄太
    • Organizer
      群馬大学生体調節研究所セミナー
    • Related Report
      2024 Annual Research Report
    • Invited
  • [Presentation] Comprehensive profiling of genomic structural variants and aberrant cytosine methylation of cancer genome using long-read sequencing2024

    • Author(s)
      Genta Nagae
    • Organizer
      FASEB meeting, Biological Methylation
    • Related Report
      2024 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional Genomics using Nanopore Sequencer2024

    • Author(s)
      Genta Nagae
    • Organizer
      Nanopore WYMM Tour: Tokyo
    • Related Report
      2024 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Comprehensive methylation analysis of pediatric liver cancer using long-read sequencing2024

    • Author(s)
      Nagae G, Aburatani H, Kato M, Hiyama E
    • Organizer
      第83回日本癌学会学術総会
    • Related Report
      2024 Annual Research Report
    • Int'l Joint Research
  • [Presentation] メチル化パネルアッセイによる多がん種同時検査システムの開発2024

    • Author(s)
      永江玄太
    • Organizer
      第8回Liquid Biopsy研究会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Whole genome and transcriptome analysis of 200 pediatric liver cancer in the JPLT study2024

    • Author(s)
      Genta Nagae
    • Organizer
      SIOPEL 2024 annula meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Long-read DNA methylation analysis of cancer genomes using a nanopore sequencing2023

    • Author(s)
      Genta Nagae
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Understanding the complex patterns of DNA modification in cancer2023

    • Author(s)
      Genta Nagae
    • Organizer
      Humang Genome Asia 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular mechanism of pediatric liver cancer -carcinogenic role of epigenetic dysregulation-2023

    • Author(s)
      Genta Nagae
    • Organizer
      日本肉腫学会第8回オープン年次学術集会プログラム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] ロングリードシーケンサーを用いた新たながんエピゲノム異常の解明2023

    • Author(s)
      永江玄太
    • Organizer
      第38回Wakoワークショップ
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Spatial dissection of cellular heterogeneity in human cancer tissues2023

    • Author(s)
      Genta Nagae
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Biological/pathological features of childhood liver tumors2023

    • Author(s)
      Nagae G
    • Organizer
      SIOPEL annual meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 小児肝がんの統合的ゲノム・エピゲノム解析による病態理解と患者層別化2022

    • Author(s)
      永江玄太
    • Organizer
      第60回日本癌治療学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Long-read DNA methylation analysis of hepatoblastoma genomes using a nanopore sequencing2022

    • Author(s)
      Nagae G, Umeda T, Ueda H, Aburatani H.
    • Organizer
      The 81th Japan Cancer Association Annual Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] メチル化パネルアッセイによる血中腫瘍DNA検出系の開発2022

    • Author(s)
      永江玄太
    • Organizer
      第42回日本分子腫瘍マーカー研究会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 小児肝がんの統合的ゲノム・エピゲノム解析による病態理解と患者層別化2022

    • Author(s)
      永江玄太
    • Organizer
      第17回北関東小児がんセミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Next future trial for childhood liver tumors2022

    • Author(s)
      Nagae G
    • Organizer
      JCCG International brainstorming session (Asia)
    • Related Report
      2022 Annual Research Report
  • [Presentation] PHITT2, the JPLT view2022

    • Author(s)
      Nagae G
    • Organizer
      SIOPEL Annual Meeting 2022
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Enhancer dysfunction related to the heterogeneity of liver and gastric malignancy2021

    • Author(s)
      Nagae G
    • Organizer
      第80回癌学会総会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] nanoDoc を用いた RNA 修飾の検出2021

    • Author(s)
      Ueda H
    • Organizer
      Virtual Nanopore Day
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2026-01-16  

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