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Elucidation of novel transcriptional targets of the DiGeorge syndrome disease gene product TBX1 and its molecular mechanisms.

Research Project

Project/Area Number 20K09901
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57020:Oral pathobiological science-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Funato Noriko  東京医科歯科大学, 統合研究機構, 准教授 (10376767)

Co-Investigator(Kenkyū-buntansha) 柴田 俊一  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (80187400)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords頭蓋底 / 軟骨結合 / microRNA / 口蓋裂 / DiGeorge 症候群 / ネアンデルタール人 / ホモ・サピエンス / 脊椎 / 上皮間葉転換 / 口唇口蓋裂 / microRNAクラスター / DiGeorge症候群 / 口蓋 / TBX1 / 頭蓋底軟骨結合 / 軟骨細胞 / 転写因子
Outline of Research at the Start

頭蓋底軟骨結合の発生や口蓋裂の発症に関わるTBX1転写因子の役割を、標的転写因子やmiRNAクラスターを含む転写制御ネットワークを通じて明らかにし、DiGeorge症候群、口蓋裂の発症に与えるTBX1の機能を解明する。各々の研究計画でin vitroおよび in vivoの手法を用いて統合的な解析を行う。

Outline of Final Research Achievements

We summarized our research on the role of TBX1 in the development of the skull base cartilage junction and published original articles and a review article (J Dent Res, 2020; Front Cell Dev Biol, 2020). We published a comprehensive review article summarizing the DiGeorge syndrome/22q11.2 deletion syndrome (J Dev Biol, 2022). We have also contributed to two books. In addition, we found that a single nucleotide polymorphism in the 22q11.2 region, which evolved from Neanderthals, may contribute to the expression of TBX1 and the characteristic cranial base morphology observed in Homo sapiens (Am J Hum Genet, 2024).

We investigated the microRNAs targeted by TBX1. We found that TBX1 targets the miR-200-ZEB2 axis in palatal formation. We then analyzed the novel function of TBX1 in epithelial-mesenchymal transition and investigated the expression and transcriptional control network of microRNAs by TBX1 both in vitro and in the palate of Tbx1 knockout mice (Funato N et al., Sci Rep, 2022).

Academic Significance and Societal Importance of the Research Achievements

本研究により、TBX1の頭蓋底軟骨結合の発生における役割や口蓋の上皮分化について明らかになった。さらに、染色体22q11.2の非コード領域にある一塩基多型rs41298798が、どのようなメカニズムでネアンデルタール人から現生人類への頭蓋底や脊椎の構造変化に関わった可能性があるかを見出した。一方、Tbx1遺伝子改変マウスに認められた頭蓋底や脊椎の変化は、TBX1を原因遺伝子とするディジョージ症候群にも認められる。そのため本研究は、ヒトの進化に加え、ヒトの疾患、頭蓋底や脊椎の発生、非コード領域に存在する一塩基多型の研究アプローチ方法、と複数の研究分野の発展に貢献することが期待される。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (30 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (4 results) Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 7 results) Presentation (8 results) (of which Int'l Joint Research: 3 results) Book (2 results) Remarks (7 results)

  • [Int'l Joint Research] Helsinki University(フィンランド)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Barcelona(スペイン)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of California(米国)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] University of California, San Francisco(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens2024

    • Author(s)
      Funato Noriko、Heliovaara Arja、Boeckx Cedric
    • Journal Title

      The American Journal of Human Genetics

      Volume: 111 Issue: 5 Pages: 939-953

    • DOI

      10.1016/j.ajhg.2024.03.012

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TBX1 targets the miR-200?ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties2022

    • Author(s)
      Funato Noriko、Yanagisawa Hiromi
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 20188-20188

    • DOI

      10.1038/s41598-022-24604-9

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a highly stable bioactive 3-hydroxyproline-containing tripeptide in human blood after collagen hydrolysate ingestion2022

    • Author(s)
      Taga Yuki、Iwasaki Yu、Tometsuka Chisa、Funato Noriko、Shigemura Yasutaka、Kusubata Masashi、Mizuno Kazunori
    • Journal Title

      npj Science of Food

      Volume: 6 Issue: 1 Pages: 29-29

    • DOI

      10.1038/s41538-022-00144-4

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Craniofacial Phenotypes and Genetics of DiGeorge Syndrome2022

    • Author(s)
      Funato Noriko
    • Journal Title

      Journal of Developmental Biology

      Volume: 10 Issue: 2 Pages: 18-18

    • DOI

      10.3390/jdb10020018

    • Related Report
      2022 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a highly stable bioactive 3-hydroxyproline-containing tripeptide in human blood after collagen hydrolysate ingestion.2022

    • Author(s)
      Yuki Taga, Yu Iwasaki, Chisa Tometsuka, Noriko Funato, Yasutaka Shigemura, Masashi Kusubata, and Kazunori Mizuno
    • Journal Title

      npj Science of Food.

      Volume: -

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-term intake of ginger protease-degraded collagen hydrolysate reduces blood lipid levels and adipocyte size in mice2021

    • Author(s)
      Tometsuka Chisa、Funato Noriko、Mizuno Kazunori、Taga Yuki
    • Journal Title

      Current Research in Food Science

      Volume: 4 Pages: 175-181

    • DOI

      10.1016/j.crfs.2021.03.003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] TBX1 regulates chondrocyte maturation in the spheno-occipital synchondrosis2020

    • Author(s)
      Funato N, Srivastava D, Shibata S, Yanagisawa H
    • Journal Title

      Journal of Dental Research

      Volume: 99 Issue: 10 Pages: 1182-1191

    • DOI

      10.1177/0022034520925080

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] New Insights Into Cranial Synchondrosis Development: A Mini Review2020

    • Author(s)
      Funato Noriko
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 8 Pages: 706-706

    • DOI

      10.3389/fcell.2020.00706

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Transcription Factor HAND1 Is Involved in Cortical Bone Mass through the Regulation of Collagen Expression2020

    • Author(s)
      Funato Noriko、Taga Yuki、Laurie Lindsay E.、Tometsuka Chisa、Kusubata Masashi、Ogawa-Goto Kiyoko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 22 Pages: 8638-8638

    • DOI

      10.3390/ijms21228638

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] DiGeorge症候群疾患遺伝子TBX1は口蓋形成においてmiR-200-ZEB2軸を標的にする2023

    • Author(s)
      船戸 紀子
    • Organizer
      第65回歯科基礎医学会学術大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] TBX1 associated with DiGeorge syndrome targets the miR-200-ZEB2 axis.2023

    • Author(s)
      Noriko Funato, Hiromi Yanagisawa.
    • Organizer
      Gordon Research Conference (Human Genetics and Genomics)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規コラーゲン由来ペプチドGly-3Hyp-4Hypの血中濃度は摂取するコラーゲン加水分解物の由来組織によって大きく異なる2022

    • Author(s)
      多賀 祐喜、岩崎 優、遠目塚 千紗、船戸 紀子、重村 泰毅、楠畑 雅、水野 一乘
    • Organizer
      第76回日本栄養・食糧学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 生姜酵素分解コラーゲンペプチドの長期摂取がもたらす脂質代謝への有益な作用2022

    • Author(s)
      遠目塚 千紗、船戸 紀子、水野 一乘、多賀 祐喜
    • Organizer
      第76回日本栄養・食糧学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] The bHLH transcription factor HAND1 is involved in cortical bone volume through the regulation of collagen expression.2020

    • Author(s)
      Noriko Funato, Yuki Taga, Lindsay E. Laurie, Chisa Tometsuka, Masashi Kusubata, Kiyoko Ogawa-Goto.
    • Organizer
      the 68th Annual Meeting of Japanese Association for Dental Research 2020.11.07 Online
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 転写因子TBX1は頭蓋底軟骨結合発生においてRUNX2下流シグナルを調節する2020

    • Author(s)
      船戸紀子、Deepak Srivastava、柴田俊一、柳沢裕美
    • Organizer
      第62回歯科基礎医学会学術大会 WEB開催 2020.9.20
    • Related Report
      2020 Research-status Report
  • [Presentation] TBX1 suppresses transcriptional activity of RUNX2 and regulates chondrocyte maturation.2020

    • Author(s)
      Funato N, Srivastava D, Shibata S, Yanagisawa H.
    • Organizer
      Cell Bio Virtual 2020-An Online ASCB|EMBO Meeting, Dec. 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] コラーゲン加水分解物経口摂取後のヒト血中における3-hydroxyproline含有トリペプチドの同定2020

    • Author(s)
      多賀祐喜、岩崎優、船戸紀子、重村泰毅、水野一乘
    • Organizer
      栄養食糧学会 2020.9.20 Web開催
    • Related Report
      2020 Research-status Report
  • [Book] Advances in Genetics Research. Vol 212022

    • Author(s)
      Kevin V. Urbano (Editor)
    • Total Pages
      159
    • Publisher
      Nova Science Publishers, Inc.
    • ISBN
      9781685075620
    • Related Report
      2021 Research-status Report
  • [Book] 細胞外マトリックス実験法2021

    • Author(s)
      新井 克彦、服部 俊治
    • Total Pages
      454
    • Publisher
      丸善出版
    • ISBN
      9784621306857
    • Related Report
      2021 Research-status Report
  • [Remarks] EurekAlert! (日本版),2024年04月

    • URL

      https://www.eurekalert.org/news-releases/1041357?language=japanese

    • Related Report
      2023 Annual Research Report
  • [Remarks] TMDU Press Release

    • URL

      https://www.tmd.ac.jp/english/press-release/20240412-1/

    • Related Report
      2023 Annual Research Report
  • [Remarks] EurekAlert!

    • URL

      https://www.eurekalert.org/news-releases/1041357/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 日本の研究.com プレスリリース

    • URL

      https://research-er.jp/articles/view/132663

    • Related Report
      2023 Annual Research Report
  • [Remarks] 東京医科歯科大学 プレスリリース

    • URL

      https://www.tmd.ac.jp/press-release/20240412-1/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 研究情報データベース 船戸紀子

    • URL

      https://reins.tmd.ac.jp/html/100007340_ja.html

    • Related Report
      2021 Research-status Report
  • [Remarks] 研究情報ベース 船戸紀子

    • URL

      https://reins.tmd.ac.jp/html/100007340_ja.html#item_kyoso_shikin_kadai_2

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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