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The role of hydroxymethylation in imprinting diseases caused by abnormal methylation

Research Project

Project/Area Number 19H03628
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution独立行政法人国立病院機構(東京医療センター臨床研究センター)

Principal Investigator

Yamazawa Kazuki  独立行政法人国立病院機構(東京医療センター臨床研究センター), その他部局等, 医長 (10338113)

Co-Investigator(Kenkyū-buntansha) 鏡 雅代  国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 室長 (70399484)
松原 圭子  国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 上級研究員 (90542952)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywordsゲノムインプリンティング / メチル化 / ヒドロキシメチル化 / 先天異常症候群
Outline of Research at the Start

本研究は、メチル化異常に起因する小児のインプリンティング異常症においてヒドロキシメチル化が病態にどのように関与しているかを解明することを目的とする、ヒト臨床検体を用いた世界初の包括的な5-ヒドロキシメチル化シトシン(5hmC)の解析研究である。不可逆的なゲノム配列の異常とは対照的に、メチル化をはじめとするエピゲノムは可塑性を持ち、治療の標的となる可能性がある。この観点から、5hmCが脱メチル化の中間代謝物であることに注目し、そのダイナミックな挙動と制御機構を明らかにすることで、新しい診断方法やメチル化・脱メチル化を制御することによるエピゲノム治療法を開発する基盤となる成果を目指す。

Outline of Final Research Achievements

The purpose of this study was to elucidate how hydroxymethylation is involved in the pathogenesis of imprinting disorders caused by methylation defects. In the course of our analysis, we identified a previously unreported methylation abnormality in a patient with growth failure and reported it as a novel imprinting disorder. In addition, methylation bead array analysis was completed in bisulfite-treated specimens from 430 cases of imprinting disorders. In the future, we plan to carry out methylation bead array analysis of oxidative bisulfite-treated specimens to elucidate the actual status of "hydroxymethylome".

Academic Significance and Societal Importance of the Research Achievements

不可逆的なゲノム配列の異常とは対照的に、メチル化をはじめとするエピゲノムは可塑性を持ち、治療の標的となる可能性がある。本研究により、ヒドロキシメチル化がインプリンティング異常症の発症に関与している可能性が示唆された。引き続きその詳細な機構を解明し、エピゲノム治療薬の開発を目指す。さらに本研究の成果は、先天性の症候群に加えて、生活習慣病や悪性腫瘍、精神疾患などの後天的なメチル化異常に起因する疾患についても診断法・治療法の開発の手がかりを与え、再生、生殖、精神医学といった多方面の生命科学分野に波及し、国民健康の増進に広く貢献することも期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (31 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 14 results,  Open Access: 8 results) Presentation (14 results) (of which Int'l Joint Research: 2 results) Book (1 results)

  • [Int'l Joint Research] University of Cambridge/Babraham Institute(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University of Cambridge/Babraham Institute(英国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma2022

    • Author(s)
      Yagi Yasuto、Abeto Naoko、Shiraishi Junichi、Miyata Chieko、Inoue Satomi、Murakami Haruka、Nakashima Moeko、Sugano Kokichi、Ushiama Mineko、Yoshida Teruhiko、Yamazawa Kazuki
    • Journal Title

      Human Genome Variation

      Volume: 9 Issue: 1

    • DOI

      10.1038/s41439-021-00180-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Frequency and clinical characteristics of distinct etiologies in patients with Silver-Russell syndrome diagnosed based on the Netchine-Harbison clinical scoring system2022

    • Author(s)
      Tomoko Fuke, Akie Nakamura, Takanobu Inoue, Sayaka Kawashima, Kaori Hara-Isono, Keiko Matsubara, Shinichiro Sano, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami
    • Journal Title

      Journal of Human Genetics

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathogenic copy number and sequence variants in children born SGA with short stature without imprinting disorders2022

    • Author(s)
      Kaori Hara-Isono, Akie Nakamura, Tomoko Fuke, Takanobu Inoue, Sayaka Kawashima, Keiko Matsubara, Shinichiro Sano, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami
    • Journal Title

      Journal of Clinical Endocrinology & Metabolism

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Japanese boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-associated retinal disorder2021

    • Author(s)
      Yamazawa Kazuki、Shimizu Kenji、Ohashi Hirofumi、Haruna Hidenori、Inoue Satomi、Murakami Haruka、Matsunaga Tatsuo、Iwata Takeshi、Tsunoda Kazushige、Fujinami Kaoru
    • Journal Title

      Human Genome Variation

      Volume: 8 Issue: 1

    • DOI

      10.1038/s41439-021-00178-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dynamics of transcription-mediated conversion from euchromatin to facultative heterochromatin at the Xist promoter by Tsix2021

    • Author(s)
      Ohhata Tatsuya、Yamazawa Kazuki、Miura-Kamio Asuka、Takahashi Saori、Sakai Satoshi、Tamura Yuka、Uchida Chiharu、Kitagawa Kyoko、Niida Hiroyuki、Hiratani Ichiro、Kobayashi Hisato、Kimura Hiroshi、Wutz Anton、Kitagawa Masatoshi
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 13 Pages: 108912-108912

    • DOI

      10.1016/j.celrep.2021.108912

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 水痘ワクチン株由来の三叉神経領域帯状疱疹を発症した6歳男児の1例2021

    • Author(s)
      坂野沙里, 三春晶嗣, 雪野祐莉子, 磯部あいこ, 影山智佳, 前田直則, 籏生なおみ, 佐藤利永子, 鈴木絵理, 山澤一樹, 藤田尚代, 込山修.
    • Journal Title

      小児科臨床

      Volume: 74 Pages: 55-59

    • NAID

      40022438926

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metacarpophalangeal pattern profile analysis for a 3‐month‐old infant with Feingold syndrome 22020

    • Author(s)
      Isobe Aiko、Maeda Naonori、Fujita Hisayo、Banno Sari、Kageyama Tomoka、Hatabu Naomi、Sato Rieko、Suzuki Eri、Miharu Masashi、Komiyama Osamu、Nakashima Moeko、Matsunaga Tatsuo、Nishimura Gen、Yamazawa Kazuki
    • Journal Title

      American Journal of Medical Genetics Part A

      Volume: 185 Issue: 3 Pages: 952-954

    • DOI

      10.1002/ajmg.a.62038

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum2020

    • Author(s)
      Fuke Tomoko、Nakamura Akie、Inoue Takanobu、Kawashima Sayaka、Hara Kaori Isono、Matsubara Keiko、Sano Shinichiro、Yamazawa Kazuki、Fukami Maki、Ogata Tsutomu、Kagami Masayo
    • Journal Title

      The Journal of Clinical Endocrinology & Metabolism

      Volume: 106 Issue: 3 Pages: 802-813

    • DOI

      10.1210/clinem/dgaa856

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide methylation analysis in Silver?Russell syndrome, Temple syndrome, and Prader?Willi syndrome2020

    • Author(s)
      Hara-Isono Kaori、Matsubara Keiko、Fuke Tomoko、Yamazawa Kazuki、Satou Kazuhito、Murakami Nobuyuki、Saitoh Shinji、Nakabayashi Kazuhiko、Hata Kenichiro、Ogata Tsutomu、Fukami Maki、Kagami Masayo
    • Journal Title

      Clinical Epigenetics

      Volume: 12 Issue: 1 Pages: 159-159

    • DOI

      10.1186/s13148-020-00949-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia2020

    • Author(s)
      Hashimoto Nobuhiro、Dateki Sumito、Suzuki Eri、Tsuchihashi Takatoshi、Isobe Aiko、Banno Sari、Kageyama Tomoka、Maeda Naonori、Hatabu Naomi、Sato Rieko、Miharu Masashi、Fujita Hisayo、Komiyama Osamu、Shimizu Hitomi、Hasegawa Tomonobu、Yamazawa Kazuki
    • Journal Title

      Human Genome Variation

      Volume: 7 Issue: 1

    • DOI

      10.1038/s41439-020-00112-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 植物ステロール摂取制限、コレスチミド、エゼチミブによる治療を7年間行っているシトステロール血症の臨床経過2020

    • Author(s)
      橋本伸弘,鈴木絵理,三春晶嗣,磯部あいこ,坂野沙里,影山智佳,前田直則,籏生なおみ,佐藤利永子,山澤一樹,藤田尚代,込山修
    • Journal Title

      小児科臨床

      Volume: 73 Pages: 1549-1553

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome2020

    • Author(s)
      Yamazawa K, Inoue T, Sakemi Y, Nakashima T, Yamashita H, Khono K, Fujita H, Enomoto K, Nakabayashi K, Hata K, Nakashima M, Matsunaga T, Nakamura A, Matsubara K, Ogata T, Kagami M
    • Journal Title

      Journal of Medical Genetics

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients2020

    • Author(s)
      Inoue T, Nakamura A, Iwahashi-Odano M, Tanase-Nakao K, Matsubara K, Nishioka J, Maruo Y, Hasegawa Y, Suzumura H, Sato S, Kobayashi Y, Murakami N, Nakabayashi K, Yamazawa K, Fuke T, Narumi S, Oka A, Ogata T, Fukami M, Kagami M
    • Journal Title

      Clinical Epigenetics

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 舌根嚢胞の1か月女児例2019

    • Author(s)
      岡田怜奈,影山智佳,前田直則,河津桃子,籏生なおみ,佐藤利永子,香取奈穂,鈴木絵理,三春晶嗣,山澤一樹,藤田尚代,込山修
    • Journal Title

      小児科臨床

      Volume: 72 Pages: 1683-1687

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] PURA症候群は先天性中枢性低換気症候群の鑑別診断である.2022

    • Author(s)
      桂美遥, 坂野沙里, 大江俊太郎, 髙田啓志, 影山智佳, 前田直則, 籏生なおみ, 佐藤利永子, 鈴木絵理, 藤田尚代, 増田怜史, 和田友香, 丸山秀彦, 鈴木俊彦, 山田洋輔, 長谷川久弥, 三春晶嗣, 山澤一樹.
    • Organizer
      第125回日本小児科学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 当院におけるBRCA1/2遺伝学的検査の現状と課題2021

    • Author(s)
      井上沙聡, 安齋純子, 安達将隆, 大木慎也, 笹岡綾子, 中小路絢子, 笹原真奈美, 山下博, 松井哲, 松永達雄, 山澤一樹.
    • Organizer
      第45回日本遺伝カウンセリング学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] DSG2遺伝子における東アジア人のfounder variantをホモ接合性に同定したARVCの一例2021

    • Author(s)
      村上遥香, 谷本陽子, 谷本耕司郎, 井上沙聡, 石川泰輔, 蒔田直昌, 山澤一樹.
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma.2021

    • Author(s)
      Yamazawa K, Yagi Y, Abeto N, Shiraishi J, Miyata C, Inoue S, Murakami H, Nakashima M, Sugano K, Ushiama M, Yoshida T.
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 2p15p16.1微細欠失症候群とRP2関連網膜症を合併した男児例.2021

    • Author(s)
      山澤一樹, 清水健司, 大橋博文, 春名英典, 井上沙聡, 村上遙香, 松永達雄, 岩田岳, 角田和繁, 藤波芳.
    • Organizer
      第44回日本小児遺伝学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A 3-month-old boy with Feingold syndrome 2: evaluation by metacarpophalangeal pattern profile analysis2021

    • Author(s)
      山澤一樹、前田直則、磯部あいこ、込山修
    • Organizer
      第43回日本小児遺伝学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 娘のBRACAnalysisを契機に未発症病的バリアント保持者であることが判明しRRSOを施行した1例.2020

    • Author(s)
      井上沙聡、安齋純子、山澤一樹、安達将隆、大木慎也、植木有紗、笹岡綾子、柵木晴妃、岩田侑子、市村佳子、笹原真奈美、山下博、松井哲、松永達雄.
    • Organizer
      第44回日本遺伝カウンセリング学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 免疫組織化学染色でMSH2/MSH6の発現低下を認めるも、MSH6遺伝子にのみ病的バリアントを呈しLynch症候群と診断された子宮体癌と大腸癌の異時性重複癌の1例.2020

    • Author(s)
      大木慎也、安達将隆、山澤一樹、植木有紗、井上沙聡、安齋純子、松永達雄、菅野康吉、山下博.
    • Organizer
      第26回日本家族性腫瘍学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features reminiscent of Silver-Russell syndrome.2020

    • Author(s)
      Kazuki Yamazawa, Takanobu Inoue, Yoshihiro Sakemi, Toshinori Nakashima, Hironori Yamashita, Kaduki Khono, Hideki Fujita, Keisuke Enomoto, Kazuhiko Nakabayashi, Kenichiro Hata, Moeko Nakashima, Tatsuo Matsunaga, Akie Nakamura, Keiko Matsubara, Tsutomu Ogata, Masayo Kagami.
    • Organizer
      European Human Genetics Virtual Conference
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features.2020

    • Author(s)
      Kazuki Yamazawa, Takanobu Inoue, Yoshihiro Sakemi, Toshinori Nakashima, Hironori Yamashita, Kaduki Khono, Hideki Fujita, Keisuke Enomoto, Kazuhiko Nakabayashi, Kenichiro Hata, Moeko Nakashima, Tatsuo Matsunaga, Akie Nakamura, Keiko Matsubara, Tsutomu Ogata, Masayo Kagami.
    • Organizer
      Genomic Imprinting - from Biology to Disease Virtual Conference
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A case of maternal uniparental disomy of chromosome 6 presenting with Silver-Russell syndrome phenotype2020

    • Author(s)
      Kazuki Yamazawa, Toru Kuboi, Tatsuya Miyoshi, Moeko Nakashima, Keiko Matsubara, Masayo Kagami.
    • Organizer
      日本人類遺伝学会第65回大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Multi-gene testingでBRCA2遺伝子の病的バリアントおよびCHEK2遺伝子の意義不明バリアントを認めた兄妹例2019

    • Author(s)
      山澤一樹、井上沙聡、安齋純子、安達将隆、松永達雄
    • Organizer
      第25回日本家族性腫瘍学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ZNF597-DMRの低メチル化に伴い胎児発育遅延を呈した1例:新規インプリンティング異常症の発見2019

    • Author(s)
      山澤一樹、井上毅信、酒見好弘、中嶋敏紀、山下博徳、河野一樹、中嶋萌子、中林一彦、秦健一郎、松原圭子、鏡雅代
    • Organizer
      第53回日本小児内分泌学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ZNF597:TSS-DMRの低メチル化に伴い胎児発育遅延を呈した1例:新規インプリンティング異常症の発見2019

    • Author(s)
      山澤一樹、井上毅信、酒見好弘、中嶋敏紀、山下博徳、河野一樹、中嶋萌子、中林一彦、秦健一郎、松原圭子、鏡雅代
    • Organizer
      日本人類遺伝学会第64回大会
    • Related Report
      2019 Annual Research Report
  • [Book] 小児疾患診療のための病態生理2-改訂第6版-2021

    • Author(s)
      山澤一樹
    • Total Pages
      1111
    • Publisher
      東京医学社
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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