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2023 Fiscal Year Annual Research Report

Target identification with systematic CRISPR-based chemical-genetic profiling in human HAP1 cells

Research Project

Project/Area Number 22H02224
Allocation TypeSingle-year Grants
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

BOONE CHARLES  国立研究開発法人理化学研究所, 環境資源科学研究センター, チームリーダー (70601342)

Co-Investigator(Kenkyū-buntansha) Pham LienThiKim  国立研究開発法人理化学研究所, 環境資源科学研究センター, 特別研究員 (50865300)
八代田 陽子  国立研究開発法人理化学研究所, 環境資源科学研究センター, 副チームリーダー (60360658)
Project Period (FY) 2022-04-01 – 2025-03-31
KeywordsTarget identification / Chemical genomics / CRISPR-Cas9
Outline of Annual Research Achievements

Natural products have long served as a valuable reservoir of compounds for drug discovery. A critical phase in drug development involves identifying the cellular targets and off-target interactions of compounds with promising bioactivities. However, our capacity to engineer or extract purified compounds from natural sources has surpassed our ability to functionally annotate them. To tackle this challenge, we are constructing a large-scale chemical-genetic network in human cells to comprehensively annotate chemical libraries. In FY2022, we established a CRISPR-Cas9-based, high-throughput chemical-genetic screening platform in human HAP1 cells. In this FY2023, this platform has been employed to assess many selected natural compounds derived the RIKEN NPDepo and the University of Tokyo DDI Core Libraries, resulting in a comprehensive compendium of chemical-genetic interaction profiles that offer valuable functional insights. This dataset represents a potent resource poised to enhance our comprehension of the druggable target space, to elucidate drug modes of action, and to identify novel drug candidates, or chemical probes to uncover novel gene functions.

Current Status of Research Progress
Current Status of Research Progress

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

Reason

In FY2023, we screened 35 natural compounds, including:
- Compounds selected through target predictions in our yeast Chemical-genomics profiling: Upon comparing the resulting chemical-genetic interactions in HAP1 cells with those in yeast cells, we observed that many compounds predicted the same target pathway as indicated by our yeast CG data.
- Reference compounds: their chemical-genetic profiles clearly indicated the expected target pathway.
- Compounds provided by our collaborators.
Also, we established a CRISPR database to make all chemical genomics profiles accessible online (currently restricted to internal access only).
Based on these findings, we have determined and implemented the approaches for target validation for potent compounds.

Strategy for Future Research Activity

In FY2023, we screened ~35 selected compounds including some reference and our collaborators’ compounds for chemical-genetic interactions using the genome-wide CRISPR-Cas9 screening platform in HAP1 cells. We have compared the resultant chemical-genetic interactions in HAP1 cells with the ones in yeast cells and the reference database of human chemical-genetic interactions. Based on that, optimal methods for target validation have been considered and carried out. In FY2024, we will continue the target validation for the compounds whose targets are previously uncharacterized, such as inhibitors for sphingolipid biosynthesis, glycosylation, etc. We will collaborate with some experts for metabolome analysis and elucidate modes-of-action of new classes of inhibitors.

Remarks

“Deadly fungi beaten with fatty acid synthase inhibitor”
https://itaintmagic.riken.jp/hot-off-the-press/deadly-fungi-beaten-with-fatty-acid-synthase-inhibitor/

  • Research Products

    (17 results)

All 2024 2023 Other

All Int'l Joint Research (2 results) Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (9 results) (of which Int'l Joint Research: 5 results,  Invited: 3 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] University of Toronto/University of British Columbia(カナダ)

    • Country Name
      CANADA
    • Counterpart Institution
      University of Toronto/University of British Columbia
  • [Int'l Joint Research] University of Minnesota(米国)

    • Country Name
      U.S.A.
    • Counterpart Institution
      University of Minnesota
  • [Journal Article] N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity.2023

    • Author(s)
      Varland S, Silva RD, Kjosas I, Faustino A, Bogaert A, Billmann M, Boukhatmi H, Kellen B, Costanzo M, Drazic A, Osberg C, Chan K, Zhang X, Tong AHY, Andreazza S, Lee JJ, Nedyalkova L, Usaj M, Whitworth AJ, Andrews BJ, Moffat J, Myers CL, Gevaert K, Boone C, Martinho RG, Arnesen T.
    • Journal Title

      Nat. Commun.

      Volume: 14 Pages: 6774

    • DOI

      10.1038/s41467-023-42342-y

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity2023

    • Author(s)
      Iyer KR, Li SC, Revie NM, Lou JW, Duncan D, Fallah S, Sanchez H, Skulska I, Usaj MM, Safizadeh H, Larsen B, Wong C, Aman A, Kiyota T, Yoshimura M, Kimura H, Hirano H, Yoshida M, Osada H, Gingras AC, Andes DR, Shapiro RS, Robbins N, Mazhab-Jafari MT, Whitesell L, Yashiroda Y, Boone C, Cowen LE.
    • Journal Title

      Cell Chem. Biol.

      Volume: 30 Pages: 795-810

    • DOI

      10.1016/j.chembiol.2023.06.005

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Overexpression profiling reveals cellular requirements in the context of genetic backgrounds and environments.2023

    • Author(s)
      Saeki N, Yamamoto C, Eguchi Y, Sekito T, Shigenobu S, Yoshimura M, Yashiroda Y, Boone C, Moriya H.
    • Journal Title

      PLoS Genetics

      Volume: 19 Pages: e1010732

    • DOI

      10.1371/journal.pgen.1010732

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The proteomic landscape of genome-wide genetic perturbations.2023

    • Author(s)
      Messner CB, Demichev V, Muenzner J, Aulakh SK, Barthel N, Rohl A, Herrera-Dominguez L, Egger AS, Kamrad S, Hou J, Tan G, Lemke O, Calvani E, Szyrwiel L, Mulleder M, Lilley KS, Boone C, Kustatscher G, Ralser M.
    • Journal Title

      Cell Chem. Biol.

      Volume: 186 Pages: 2018-2034.e21

    • DOI

      10.1016/j.cell.2023.03.026

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 分裂酵母Schizosaccharomyces pombeにおいてペンタデカン酸が誘導する脂肪毒性2024

    • Author(s)
      星川陽次郎、代田夏帆、松山晃久、木村聡、Sheena LI 、八代田陽子、Charles BOONE、津川裕司、有田誠、吉田稔、西村慎一
    • Organizer
      日本農芸化学会2024年度大会
  • [Presentation] エルゴステロール合成経路を標的とする抗真菌薬の開発2024

    • Author(s)
      八代田陽子
    • Organizer
      東京大学医科学研究所-千葉大学真菌医学研究センター 国際共同研究・共同研究拠点事業 2023年度 成果報告会
    • Invited
  • [Presentation] Exogenous pentadecanoic acid perturbs the membrane lipid profile to generate the giant endoplasmic reticulum sheet2023

    • Author(s)
      Hoshikawa Y, Matsuyama A, Li S, Yashiroda Y, Boone C, Tsugawa H, Arita M, Yoshida M, Nishimura S.
    • Organizer
      The 11th International Fission Yeast Meeting (Pombe 2023)
    • Int'l Joint Research
  • [Presentation] Mapping genetic and chemical-genetic networks in yeast2023

    • Author(s)
      Boone CM.
    • Organizer
      31st International Conference on Yeast Genetics and Molecular Biology (ICYGMB31)
    • Int'l Joint Research / Invited
  • [Presentation] 抗真菌剤ポアシジエンは細胞質鉄イオンの蓄積を引き起こす2023

    • Author(s)
      趙天宇、小川樹、吉村麻美、八代田陽子、Charles Boone
    • Organizer
      酵母遺伝学フォーラム第56回研究報告会
  • [Presentation] 抗真菌剤NPD2560の細胞内作用機序に関する研究2023

    • Author(s)
      劉薇、関口宙暉、山中大輔、八代田陽子、Sheena Li 、Charles Boone 、一刀かおり、大矢禎一
    • Organizer
      酵母遺伝学フォーラム第56回研究報告会
  • [Presentation] Mapping genetic interaction networks in yeast and human cells2023

    • Author(s)
      Boone CM.
    • Organizer
      The 2023 Cold Spring Harbor Asia Conference, Yeast and Life Sciences
    • Int'l Joint Research / Invited
  • [Presentation] Identification of potential therapeutic lead compounds targeting serine-palmitoyltransferase2023

    • Author(s)
      Pham L, Yoshimura M, Yashiroda Y, Li S, Usaj M, Burke RM, oshida M, Boone C.
    • Organizer
      The 2023 Cold Spring Harbor Asia Conference, Yeast and Life Sciences
    • Int'l Joint Research
  • [Presentation] Mode-of-action analysis of inhibitors targeting ergosterol2023

    • Author(s)
      Yashiroda Y, Yoshimura M, Usui M, Kimura H, Isuhuaylas LAV, Pham LTK, Niwa T, Takahashi I, Hosoya T, Ilies L, Yoshida M, Boone C.
    • Organizer
      The 2023 Cold Spring Harbor Asia Conference, Yeast and Life Sciences
    • Int'l Joint Research
  • [Remarks] 脂肪酸合成を阻害する新たな抗真菌化合物の発見-世界的脅威である真菌感染症の新しい治療薬として期待-

    • URL

      https://www.riken.jp/press/2023/20230711_1/index.html

  • [Patent(Industrial Property Rights)] Compounds as antifungal agents, derivatives thereof and novel compounds2023

    • Inventor(s)
      Oya, Yashiroda, Boone, et al.
    • Industrial Property Rights Holder
      Oya, Yashiroda, Boone, et al.
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      63/578668
    • Overseas

URL: 

Published: 2024-12-25  

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