A chemical genomics approach for understanding chemical communication

2018 Fiscal Year Annual Research Report

• Project Area: Frontier research of chemical communications
• Project/Area Number: 17H06411
• Research Institution: Institute 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): 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, 専任研究員 (60360658)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Keywords: chemical genomics / yeast / chemical communication

Outline of Annual Research Achievements

To more precisely link bioactive compounds to their target molecules, we set up the pipeline consisting of the TS (~1,100 strains), HET (~970 strains), WG (~3,000 strains), and MoBY (~960 strains) collections and screened highly bioactive compounds to obtain their chemical genomic profiles. We also isolated ~90 spontaneous drug-resistant mutants for ~40 bioactive compounds and identified mutation sites by next-generation sequencing. This workflow successfully predicted targets of some of the highly bioactive compounds. For example, one compound has a precise HET interaction with FAS1 (fatty acid synthase), and a drug-resistant mutant for the compound shows a non-synonymous SNP in the same gene. Supplementation with fatty acids rescues the compound toxicity, so it is likely that the compound directly targets Fas1.
We planned to construct a drug screening system for the suppressor (SUP) double mutant collection. We tried several pilot experiments using the SUP collection and target-known compounds and found that it did not seem to work properly. However, we confirmed that our chemical genomic pipeline (chemical genomic analysis using the HET, TS, WG and MoBY libraries and drug-resistant mutants) has so far efficiently identified/predicted targets of some of the highly bioactive compounds from the NPDepo library, even without the SUP library.
Furthermore, we developed two scalable computational tools (BEAN-counter and CG-TARGET) to assist in both generating and interpreting chemical genomic interaction profiles as part of our collaboration with University of Minnesota.

Current Status of Research Progress

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

Reason

We almost established chemical genomic pipeline (chemical genomic analysis using the HET, TS, WG and MoBY libraries and drug-resistant mutants) that has so far efficiently identified/predicted targets of the highly bioactive compounds from the NPDepo library.

Strategy for Future Research Activity

We will fine-adjust the chemical genomic pipeline (chemical genomic analysis using the HET, TS, WG and MoBY libraries and drug-resistant mutants) and using the pipeline we will conduct target identification analysis of the Group A01/A02 collaborators’ compounds. We will also screen highly bioactive compounds from a new set of the NPDepo compounds (~10,000) to do target identification analysis.

Research Products

• [Int'l Joint Research] トロント大学/マギル大学/ブリティッシュコロンビア大学(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: トロント大学/マギル大学/ブリティッシュコロンビア大学
• [Int'l Joint Research] ミネソタ大学/Yumanity(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: ミネソタ大学/Yumanity
• [Int'l Joint Research] National Center for Drug Screening(中国)
  • Country Name: CHINA
  • Counterpart Institution: National Center for Drug Screening
• [Journal Article] Using BEAN-counter to quantify genetic interactions from multiplexed barcode sequencing experiments (2019)
  • Author(s): Simpkins SW, Deshpande R, Nelson J, Li SC, Piotrowski JS, Ward HN, Yashiroda Y, Osada H, Yoshida M, Boone C, Myers CL
  • Journal Title: Nature Protocols Volume: 14 Pages: 415-440
  • DOI: 10.1038/s41596-018-0099-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Predicting bioprocess targets of chemical compounds through integration of chemical-genetic and genetic interactions (2018)
  • Author(s): Simpkins SW, Nelson J, Deshpande R, Li SC, Piotrowski JS, Wilson EH, Gebre AA, Safizadeh H, Okamoto R, Yoshimura M, Costanzo M, Yashiroda Y, Ohya Y, Osada H, Yoshida M, Boone C, Myers CL
  • Journal Title: PLoS Computational Biology Volume: 14 Pages: e1006532
  • DOI: 10.1371/journal.pcbi.1006532
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Yeast chemical genomics approach for target identification (2019)
  • Author(s): 八代田 陽子
  • Organizer: The 5th CSRS-ITbM Joint Workshop
• [Presentation] Yeast Chemical Genomic Approach for Target Identification (2019)
  • Author(s): Yoko Yashiroda
  • Organizer: ACBI 2019 Yangon Meeting
  • Int'l Joint Research / Invited
• [Presentation] Target identification using an integrated chemical genomic approach (2019)
  • Author(s): Sheena Li, Mami Yoshimura, Hamid Safizadhe, Scott Simpkins, Justin Nelson, Yuichi Shichino, Yoko Yashiroda, Shintaro Iwasaki, Hiroyuki Hirano, Hiroyuki Osada, Minoru Yoshida, Chad Myers, Charles Boone
  • Organizer: The 1st International Symposium on Chemical Communication (ISCC2019)
  • Int'l Joint Research
• [Presentation] Identification of an inhibitor of the yeast fatty acid synthase (2019)
  • Author(s): Yoko Yashiroda, Sheena Claire Li, Mami Yoshimura, Hiromi Kimurs, Norio Kudo, Hamid Safizadhe, Scott Simpkins, Justin Nelson, Hiroyuki Hirano, Hiroyuki Osada, Minoru Yoshida, Chad Myers, Charles Boone
  • Organizer: The 1st International Symposium on Chemical Communication (ISCC2019)
  • Int'l Joint Research
• [Presentation] Target identification using an integrated chemical genetic approach (2018)
  • Author(s): Sheena Li
  • Organizer: Yeast Genetics Meeting
  • Int'l Joint Research
• [Presentation] Target integration using an integrated chemcial genetic approach (2018)
  • Author(s): Li Sheena, Boone Charles
  • Organizer: 新学術領域研究（研究領域提案型）「化学コミュニケーションのフロンティア」第3回公開シンポジウム