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Unraveling mechanism of pathogenesis in CHAREGE syndrome using iPSC-derived brain organoid

Research Project

Project/Area Number 19H03623
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 InstitutionKeio University

Principal Investigator

KOHYAMA JUN  慶應義塾大学, 医学部(信濃町), 准教授 (30437511)

Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
KeywordsCHARGE症候群 / 脳オルガノイド / iPS細胞 / エピジェネティクス / iPS細胞由来脳オルガノイド / エンハンサー制御 / CHARGE症候群 / iPS細胞由来脳オルガノイド溝田 / 1細胞RNA-Seq / 1細胞ATAC-Seq
Outline of Research at the Start

CHARGE症候群は複数の臓器において発達異常や発生異常が見出される疾患である。その原因遺伝子CHD7はエンハンサー制御を司る遺伝子であり、中枢神経系においては神経系特異的エンハンサー領域においてその活性を制御する因子である。本研究課題においては脳オルガノイドを用い、CHARGE症候群の中枢神経系症状を詳細に解析し、エピゲノム制御による治療法開発への基礎的基盤を構築する。

Outline of Final Research Achievements

Using iPS cells derived from CHARGE syndrome patients, the research involved brain organoid models to investigate the epigenomic regulatory mechanisms of CHD7's target genes. Methods included histological examination and single-cell level RNA-Seq analyses to explore the target genes and epigenomic states influenced by CHD7. The study found that CHD7 binds with tissue-specific pioneer factors to regulate enhancer activation and identified abnormalities in glial cell maturation. Additionally, a novel factor, Factor X, was discovered to interact with CHD7, forming droplets in the nucleus, particularly in neural progenitor cells, concentrating transcriptional activators and positively regulating CHD7 activity. Inhibition of this droplet formation in Factor X resulted in phenotypes similar to those of CHARGE syndrome patients' iPS cells, suggesting new mechanisms in CHD7 function.

Academic Significance and Societal Importance of the Research Achievements

CHD7遺伝子と関連因子の機能解明により、早期診断や適切な治療法の開発が進むことで、患者の生活の質向上や医療費削減が期待される。また、遺伝的リスクを抱える家族への正確な情報提供や、エピゲノム制御と転写調節の新たな知見の提供を通じて、他の神経発生障害の理解や治療法開発にも寄与する可能性がある。これにより、CHARGE症候群患者やその家族が病気を理解し、対処するための支援が強化され、社会全体の理解が深まることが期待される。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (11 results)

All 2024 2023 2022 2020

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 7 results)

  • [Journal Article] Human-induced pluripotent stem cell-derived neural stem/progenitor cell ex vivo gene therapy with synaptic organizer CPTX for spinal cord injury2024

    • Author(s)
      Saijo Y, Nagoshi N, Kawai M, Kitagawa T, Suematsu Y, Ozaki M, Shinozaki M, Kohyama J, Shibata S, Takeuchi K, Nakamura M, Yuzaki M, Okano H.
    • Journal Title

      Stem Cell Reports.

      Volume: 19 Issue: 3 Pages: 100393-100393

    • DOI

      10.1016/j.stemcr.2024.01.007

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mesenchymal properties of iPSC-derived neural progenitors that generate undesired grafts after transplantation2023

    • Author(s)
      Isoda Miho、Sanosaka Tsukasa、Tomooka Ryo、Mabuchi Yo、Shinozaki Munehisa、Andoh-Noda Tomoko、Banno Satoe、Mizota Noriko、Yamaguchi Ryo、Okano Hideyuki、Kohyama Jun
    • Journal Title

      Communications Biology

      Volume: 6 Issue: 1 Pages: 611-611

    • DOI

      10.1038/s42003-023-04995-9

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spatial heterogeneity of bone marrow endothelial cells unveils a distinct subtype in the epiphysis2023

    • Author(s)
      Iga Takahito、Kobayashi Hiroshi、Kusumoto Dai、Sanosaka Tsukasa、Fujita Nobuyuki、Tai-Nagara Ikue、Ando Tomofumi、Takahashi Tomoko et.al
    • Journal Title

      Nature Cell Biology

      Volume: 25 Issue: 10 Pages: 1415-1425

    • DOI

      10.1038/s41556-023-01240-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Current status and prospects of regenerative medicine for spinal cord injury using human induced pluripotent stem cells: a review2023

    • Author(s)
      Inoue Mitsuhiro、Yamaguchi Ryo、He Ching Chi Jimmy、Ikeda Atsushi、Okano Hideyuki、Kohyama Jun
    • Journal Title

      Stem Cell Investigation

      Volume: 10 Pages: 6-6

    • DOI

      10.21037/sci-2022-037

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Chromatin remodeler CHD7 targets active enhancer region to regulate cell type-specific gene expression in human neural crest cells.2022

    • Author(s)
      Tsukasa Sanosaka, Hironobu Okuno, Noriko Mizota, Tomoko Andoh-Noda, Miki Sato, Ryo Tomooka, Satoe Banno, Jun Kohyama, Hideyuki Okano.
    • Journal Title

      Scientific reports

      Volume: 12 Issue: 1 Pages: 22648-22648

    • DOI

      10.1038/s41598-022-27293-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human PSCs determine the competency of cerebral organoid differentiation via FGF signaling and epigenetic mechanisms2022

    • Author(s)
      Ideno Hirosato、Imaizumi Kent、Shimada Hiroko、Sanosaka Tsukasa、Nemoto Akisa、Kohyama Jun、Okano Hideyuki
    • Journal Title

      iScience

      Volume: 25 Issue: 10 Pages: 105140-105140

    • DOI

      10.1016/j.isci.2022.105140

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A non-invasive system to monitor in vivo neural graft activity after spinal cord injury2022

    • Author(s)
      Ago K、Nagoshi N、Imaizumi K、Kitagawa T、Kawai M、Kajikawa K、Shibata R、Kamata Y、Kojima K、Shinozaki M、Kondo T、Iwano S、Miyawaki A、Ohtsuka M、Bito H、Kobayashi K、Shibata S、Shindo T、Kohyama J、Matsumoto M、Nakamura M、Okano H
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 803-803

    • DOI

      10.1038/s42003-022-03736-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coupling of angiogenesis and odontogenesis orchestrates tooth mineralization in mice2022

    • Author(s)
      Matsubara T, Iga T, Sugiura Y, Kusumoto D, Sanosaka T, Tai-Nagara I, Takeda N, Fong GH, Ito K, Ema M, Okano H, Kohyama J, Suematsu M, *Kubota Y.
    • Journal Title

      J Exp Med

      Volume: 219 Issue: 4

    • DOI

      10.1084/jem.20211789

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Administration of C5a Receptor Antagonist Improves the Efficacy of Human Induced Pluripotent Stem Cell Derived Neural Stem/Progenitor Cell Transplantation in the Acute Phase of Spinal Cord Injury2022

    • Author(s)
      Shibata Reo、Nagoshi Narihito、Kajikawa Keita、Ito Shuhei、Shibata Shinsuke、Shindo Tomoko、Khazaei Mohamad、Nori Satoshi、Kohyama Jun、Fehlings Michael G.、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki
    • Journal Title

      Journal of Neurotrauma

      Volume: 39 Issue: 9-10 Pages: 667-682

    • DOI

      10.1089/neu.2021.0225

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Modulation by DREADD reveals the therapeutic effect of human iPSC-derived neuronal activity on functional recovery after spinal cord injury2022

    • Author(s)
      Kitagawa Takahiro、Nagoshi Narihito、Kamata Yasuhiro、Kawai Momotaro、Ago Kentaro、Kajikawa Keita、Shibata Reo、Sato Yuta、Imaizumi Kent、Shindo Tomoko、Shinozaki Munehisa、Kohyama Jun、Shibata Shinsuke、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki
    • Journal Title

      Stem Cell Reports

      Volume: 17 Issue: 1 Pages: 127-142

    • DOI

      10.1016/j.stemcr.2021.12.005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury2020

    • Author(s)
      Kamata Yasuhiro、Isoda Miho、Sanosaka Tsukasa、Shibata Reo、Ito Shuhei、Okubo Toshiki、Shinozaki Munehisa、Inoue Mitsuhiro、Koya Ikuko、Shibata Shinsuke、Shindo Tomoko、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki、Nagoshi Narihito、Kohyama Jun
    • Journal Title

      STEM CELLS Translational Medicine

      Volume: 10 Issue: 3 Pages: 398-413

    • DOI

      10.1002/sctm.20-0269

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed

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Published: 2019-04-18   Modified: 2025-01-30  

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