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Genomic modalities of development and differentiation and elucidation of disease mechanisms by their malfunction

Planned Research

Project AreaGenome modality: understanding physical properties of the genome
Project/Area Number 20H05940
Research Category

Grant-in-Aid for Transformative Research Areas (A)

Allocation TypeSingle-year Grants
Review Section Transformative Research Areas, Section (III)
Research InstitutionThe University of Tokyo

Principal Investigator

白髭 克彦  東京大学, 定量生命科学研究所, 教授 (90273854)

Co-Investigator(Kenkyū-buntansha) 泉 幸佑  東京大学, 定量生命科学研究所, 客員准教授 (40383707)
朴 聖俊  東京大学, 医科学研究所, 准教授 (40759411)
Project Period (FY) 2020-11-19 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥140,140,000 (Direct Cost: ¥107,800,000、Indirect Cost: ¥32,340,000)
Fiscal Year 2024: ¥28,600,000 (Direct Cost: ¥22,000,000、Indirect Cost: ¥6,600,000)
Fiscal Year 2023: ¥28,600,000 (Direct Cost: ¥22,000,000、Indirect Cost: ¥6,600,000)
Fiscal Year 2022: ¥28,600,000 (Direct Cost: ¥22,000,000、Indirect Cost: ¥6,600,000)
Fiscal Year 2021: ¥27,040,000 (Direct Cost: ¥20,800,000、Indirect Cost: ¥6,240,000)
Fiscal Year 2020: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000)
Keywords希少疾患 / コヒーシン / コヒーシンローダー / Hi-C / 転写伸長 / 転写制御ネットワーク / Cbx1 / NKAP / Brd4 / Aff4 / Hexim / Brd
Outline of Research at the Start

ゲノム上の局在部位の違いによってコヒーシンはそれぞれ別の機能を果たしていると考えられているが、その実態はまだ明らかではなく、どのようにゲノム上でコヒーシンの機能が使い分けられているのか、それを規定する因子は何なのかも含め大きな謎である。また、コヒーシンのいずれの機能の破綻が疾患の病態に寄与しているのかも依然として不明である。本研究ではCdLS関連疾患の患者由来のiPSおよび、疾患モデル細胞を用いた実験系とin vitro 転写再構成系を併用し、コヒーシン関連因子の発生・分化における役割をゲノム学と遺伝学、生化学を動員して明らかにすることを目指す。

Outline of Annual Research Achievements

白髭班は、発生・分化異常を示す遺伝性疾患として知られているコヒーシン病の関連因子による転写制御機構について、DNA物性・モダリティ制御因子の特性と関連づけて明らかにすることを目標としている。これまでに、コヒーシン病の患者に由来する細胞株における次世代シークエンシング解析を中心とした実験を実施し、コヒーシンが転写のモダリティ制御ネットワークを適切にチューニングしており、その破綻が転写異常に繋がることが明らかとなった(論文投稿準備中)。また、朴らがコヒーシン及ひその関連因子による転写制御ネットワークについて大規模なデータ解析を行い、数理モデリング手法の開発等についての成果を論文報告した(NAR Genomics and Bioinformatics 2024; Nature Genetics 2024)。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

データベースの整備も順調に進んでおり、最終的な目標は達成されるみ込みが立った。論文発表も順調である。

Strategy for Future Research Activity

Aff4のupregulationとNIPBLのdown regulationがコヒーシン病の特徴であることが判明してきた。この点をより分子的な実態として明らかにしたいと考えており、そのために今後はAff4-NIPBLを含む複合体の転写の活性化に伴う変遷を生化学的に再構成系を用いて明らかにしたいと考えている。一方で、コヒーシンの欠損が引き起こす転写異常の実態としてRNAの構造異常が明らかになってきている。コヒーシン病患者についてもRNAの構造について解析を進め病態を明確にしていきたい。

Report

(4 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (6 results) Journal Article (22 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 22 results,  Open Access: 22 results) Presentation (8 results) (of which Int'l Joint Research: 5 results,  Invited: 8 results)

  • [Int'l Joint Research] Children's Hospital of Philadelphia(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] カロリンスカ研究所(スウェーデン)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Center for Biological Research(スペイン)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Children's Hospital of Philadelphia(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] カロリンスカ研究所(スウェーデン)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Center for Biological Research(スペイン)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] A computational approach for deciphering the interactions between proximal and distal gene regulators in GC B-cell response2024

    • Author(s)
      Sung-Joon Park* and Kenta Nakai
    • Journal Title

      NAR Genomics and Bioinformatics lqae050

      Volume: -

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility2024

    • Author(s)
      Ishii Satoko、Kakizuka Taishi、Park Sung-Joon、Tagawa Ayako、Sanbo Chiaki、Tanabe Hideyuki、Ohkawa Yasuyuki、Nakanishi Mahito、Nakai Kenta、Miyanari Yusuke
    • Journal Title

      Nature Genetics

      Volume: 56 Issue: 3 Pages: 473-482

    • DOI

      10.1038/s41588-024-01658-1

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors2023

    • Author(s)
      Nakato Ryuichiro、Sakata Toyonori、Wang Jiankang、Nagai Luis Augusto Eijy、Nagaoka Yuya、Oba Gina Miku、Bando Masashige、Shirahige Katsuhiko
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 5647-5647

    • DOI

      10.1038/s41467-023-41316-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits.2023

    • Author(s)
      Sorimachi Y, Kobayashi H, Shiozawa Y, Koide S, Nakato R, Shimizu Y, Okamura T, Shirahige K, Iwama A, Goda N, Takubo K, Takubo K.
    • Journal Title

      Stem Cell Reports

      Volume: S2213-6711(23) Issue: 5 Pages: 00097-8

    • DOI

      10.1016/j.stemcr.2023.03.009

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transient Methionine Deprivation Triggers Histone Modification and Potentiates Differentiation of Induced Pluripotent Stem Cells.2023

    • Author(s)
      Ozawa H, Kambe A, Hibi K, Murakami S, Oikawa A, Handa T, Fujiki K, Nakato R, Shirahige K, Kimura H, Shiraki N, Kume S
    • Journal Title

      Stem Cells.

      Volume: 41(3) Issue: 3 Pages: 271-286

    • DOI

      10.1093/stmcls/sxac082

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cohesin-dependent chromosome loop extrusion is limited by transcription and stalled replication forks.2022

    • Author(s)
      Jeppsson K, Sakata T, Nakato R, Milanova S, Shirahige K, Bjorkegren C.
    • Journal Title

      Sci Adv.

      Volume: 8(23) Issue: 23

    • DOI

      10.1126/sciadv.abn7063

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation.2022

    • Author(s)
      Wang J, Bando M, Shirahige K, Nakato R.
    • Journal Title

      Nat Commun

      Volume: 13(1) Issue: 1 Pages: 3218-3218

    • DOI

      10.1038/s41467-022-30792-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expanding the phenotypic spectrum of ARCN1-related syndrome.2022

    • Author(s)
      Ritter AL, et.al
    • Journal Title

      Genet Med.

      Volume: S1098-3600 Issue: 6 Pages: 00651-7

    • DOI

      10.1016/j.gim.2022.02.005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inborn error of metabolism patients after liver transplantation: Outcomes of 35 patients over 27 years in one pediatric quaternary hospital.2022

    • Author(s)
      Pritchard AB, Izumi K, Payan-Walters I, Yudkoff M, Rand EB, Bhoj E.
    • Journal Title

      Am J Med Genet A.

      Volume: 188(5) Issue: 5 Pages: 1443-1447

    • DOI

      10.1002/ajmg.a.62659

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.2022

    • Author(s)
      Kumble S, et.al
    • Journal Title

      Hum Mutat.

      Volume: 43(2) Issue: 2 Pages: 266-282

    • DOI

      10.1002/humu.24308

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Diagnostic Outcomes from 700 Cases: What Can We Learn from a Retrospective Analysis of Clinical Exome Sequencing?2022

    • Author(s)
      Murrell JR, et.al
    • Journal Title

      J Mol Diagn.

      Volume: 24(3) Issue: 3 Pages: 274-286

    • DOI

      10.1016/j.jmoldx.2021.12.002

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Highly rigid H3.1/H3.2-H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells2022

    • Author(s)
      Hada M, Miura H, Tanigawa A, Matoba S, Inoue K, Ogonuki N, Hirose M, Watanabe N, Nakato R, Fujiki K, Hasegawa A, Sakashita A, Okae H, Miura K, Shikata D, Arima T, Shirahige K, Hiratani I, Ogura A.
    • Journal Title

      Genes Dev

      Volume: 36 Issue: 1-2 Pages: 84-102

    • DOI

      10.1101/gad.348782.121

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterizing promoter and enhancer sequences by a deep learning method2021

    • Author(s)
      Xin Zeng, Sung-Joon Park and Kenta Nakai
    • Journal Title

      Frontiers in Genetics

      Volume: 12 Pages: 681259-681259

    • DOI

      10.3389/fgene.2021.681259

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation.2021

    • Author(s)
      Polla DL, et.al
    • Journal Title

      Am J Hum Genet.

      Volume: 108(7) Pages: 1342-1349

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.2021

    • Author(s)
      Sheppard SE, et.al
    • Journal Title

      Am J Med Genet A.

      Volume: - Issue: 6 Pages: 1649-1665

    • DOI

      10.1002/ajmg.a.62124

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Variants in NAA15 cause pediatric hypertrophic cardiomyopathy.2021

    • Author(s)
      Ritter A, Berger JH, Deardorff M, Izumi K, Lin KY, Medne L, Ahrens-Nicklas RC.
    • Journal Title

      Am J Med Genet A.

      Volume: 185(1) Pages: 228-233

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Single-cell transcriptional analysis reveals developmental stage-dependent changes in retinal progenitors in the murine early optic vesicle2021

    • Author(s)
      Yamada R, Oguri A, Fujiki K, Shirahige K, Takezoe H, Takahashi N, Kanai Y.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 543 Pages: 80-86

    • DOI

      10.1016/j.bbrc.2021.01.043

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional control of Eco1 through the MCM complex in sister chromatid cohesion.2021

    • Author(s)
      Yoshimura A, Sutani T, Shirahige K.
    • Journal Title

      Gene.

      Volume: 784 Pages: 145584-145584

    • DOI

      10.1016/j.gene.2021.145584

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer2021

    • Author(s)
      Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, et. al.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 35

    • DOI

      10.1073/pnas.2025647118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Codependency and mutual exclusivity for gene community detection from sparse single-cell transcriptome data2021

    • Author(s)
      Nakajima N, Hayashi T, Fujiki K, Shirahige K, Akiyama T, Akutsu T, Nakato R.
    • Journal Title

      Nucleic Acids Res

      Volume: 49 Issue: 18 Pages: e104-e104

    • DOI

      10.1093/nar/gkab601

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bioinformatical dissection of fission yeast DNA replication origins2020

    • Author(s)
      Koji Masuda, Claire Renard-Guillet, Katsuhiko Shirahige, Takashi Sutani
    • Journal Title

      Open Biol .

      Volume: Volume 10Issue 7 Issue: 7 Pages: 200052-200052

    • DOI

      10.1098/rsob.200052

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence2020

    • Author(s)
      Olan Ioana、Parry Aled J.、Schoenfelder Stefan、Narita Masako、Ito Yoko、Chan Adelyne S. L.、Slater Guy St.C.、Bihary Dora、Bando Masashige、Shirahige Katsuhiko、Kimura Hiroshi、Samarajiwa Shamith A.、Fraser Peter、Narita Masashi
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 6049-6049

    • DOI

      10.1038/s41467-020-19878-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Is Cohesin Really Necessary for Transcription?2023

    • Author(s)
      Katsuhiko Shirahige
    • Organizer
      ロッテルダム大学 セミナー
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Is Cohesin Really Necessary for Transcription?2023

    • Author(s)
      Katsuhiko Shirahige
    • Organizer
      CdLS Meeting (イタリア シエナ)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Is Cohesin Really Necessary for Transcription?2023

    • Author(s)
      Katsuhiko Shirahige
    • Organizer
      ウィーン大学セミナー
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Is Cohesin Really Necessary for Transcription?2023

    • Author(s)
      Katsuhiko Shirahige
    • Organizer
      Cohesinopathy Symposium (スペイン ザラゴザ)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Is Cohesin Really Necessary for Transcription?2023

    • Author(s)
      Katsuhiko Shirahige
    • Organizer
      生命ダイナミクスシンポジウム(台湾大学)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 染色体の謎に迫る ―命のプラットフォーム、染色体の構造と機能を解き明かす―2021

    • Author(s)
      白髭克彦
    • Organizer
      2021年度 第3回創発セミナー(大隅基礎科学創成財団)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 転写制御におけるコヒーシンの役割2021

    • Author(s)
      白髭克彦
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] THE FUNCTION OF COHESIN IN THE ASSEMBLY OF TRANSCRIPTIONAL MACHINERY IN VIVO AND IN VITRO2021

    • Author(s)
      白髭克彦
    • Organizer
      Cold Spring harbor Asia, DNA Metabolism, Genomic Stability and Diseases
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2020-11-24   Modified: 2024-12-25  

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