Building a Predictive Mathematical Platform for RNA Modification Structure and Function

• Project/Area Number: 23K24941
• Project/Area Number (Other): 22H03686 (2022-2023)
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund (2024); Single-year Grants (2022-2023)
• Section: 一般
• Review Section: Basic Section 62010:Life, health and medical informatics-related
• Research Institution: National Institute of Advanced Industrial Science and Technology (2024); Nagoya University (2022-2023)
• Principal Investigator: Koseki Jun 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (20616669)
• Co-Investigator(Kenkyū-buntansha): 今野 雅允 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (80618207)
• Project Period (FY): 2024-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2024: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2023: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2022: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: RNA修飾 / 構造変化 / 機能変化 / 理論科学 / 位相幾何学

Outline of Research at the Start

生体内分子の『構造と機能』の間には非常に強い相関がある。生体分子に修飾基が入ることで、自身の構造変化や結合分子との相互作用変化が誘導され、生体内機能が変化する可能性が報告されている。今日までに非常に多くのタンパク質や核酸の置換基修飾が報告されているが、『構造変化』と『機能変化』との関係性は未だに解明されていない。そこで本申請研究では『構造と機能』に対する数理科学的解析基盤を構築することで、生命医科学・科学等の分野で着目されてきた、『構造変化』に付随する『機能変化』予測の自動化を目指す。目的達成のために理論科学的手とデータ解析手法を融合・発展させる。さらに理論的予測結果を実験的にも検証する。

Outline of Final Research Achievements

Because of the strong correlation between structure and function in biomolecules, it has been reported that chemical modifications can induce structural changes and alter molecular interactions, thereby affecting biological function.
We developed a predictive platform based on persistent homology, a method from topological data analysis, to extract how subtle structural changes - such as the presence or absence of chemical modifications - can lead to significant changes in molecular interactions and overall molecular structure. This platform can also detect changes in hydrogen bonding and CH-π interactions that mediate the propagation of structural changes throughout the molecule.
As a result, our approach enables the quantitative interpretation and prediction of the relationship between structure and function in modified biomolecules.

Academic Significance and Societal Importance of the Research Achievements

生体内分子の『構造と機能』の関係性を抽出するための手法として、Dynamical Analysis of Interaction and Structural changes (DAIS)法を確立した。本手法はウイルスの感染力に及ぼす影響や、アミノ酸変異がもたらす機能変化、薬剤耐性等に応用可能である。
実際にRNA修飾の機能変化のみにかかわらず、SARS-CoV-2増殖を抑制するレムデシビルの薬剤耐性要因の可能性を示すことにも成功しており、近年問題視されているウイルス感染症に対するアミノ酸変異の影響を考慮した臨床研究分野にも寄与できる手法として確立できたため、その社会的意義は大きいと考えられる。

Research Products

• [Journal Article] Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages. (2025)
  • Author(s): Sato T, Sugiyama D, Koseki J,・・・（7名）・・・, Kiyoi H, Nishikawa H
  • Journal Title: JCI Insight Volume: 10 Issue: 1
  • DOI: 10.1172/jci.insight.178146
  • Peer Reviewed / Open Access
• [Journal Article] Survivability and life support in sealed mini-ecosystems with simulated planetary soils (2024)
  • Author(s): Sato Tsubasa、Abe Ko、Koseki Jun、Seto Mayumi、Yokoyama Jun、Akashi Tomohiro、Terada Masahiro、Kadowaki Kohmei、Yoshida Satoshi、Yamashiki Yosuke Alexandre、Shimamura Teppei
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 26322-26322
  • DOI: 10.1038/s41598-024-75328-x
  • Peer Reviewed / Open Access
• [Journal Article] Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis (2024)
  • Author(s): Hashimoto Masahiro、Kojima Yasuhiro et. al.
  • Journal Title: eBioMedicine Volume: 103 Pages: 105102-105102
  • DOI: 10.1016/j.ebiom.2024.105102
  • Peer Reviewed / Open Access
• [Journal Article] Topological data analysis of protein structure and inter/intra-molecular interaction changes attributable to amino acid mutations (2023)
  • Author(s): Koseki Jun、Hayashi Shuto、Kojima Yasuhiro、Hirose Haruka、Shimamura Teppei
  • Journal Title: Computational and Structural Biotechnology Journal Volume: 21 Pages: 2950-2959
  • DOI: 10.1016/j.csbj.2023.05.009
  • Peer Reviewed / Open Access
• [Journal Article] Metastases and treatment-resistant lineages in patient-derived cancer cells of colorectal cancer (2023)
  • Author(s): Fujino Shiki、Miyoshi Norikatsu、Ito Aya、Hayashi Rie、Yasui Masayoshi、Matsuda Chu、Ohue Masayuki、Horie Masafumi、Yachida Shinichi、Koseki Jun、Shimamura Teppei、Hata Tsuyoshi、Ogino Takayuki、Takahashi Hidekazu、Uemura Mamoru、Mizushima Tsunekazu、Doki Yuichiro、Eguchi Hidetoshi
  • Journal Title: Communications Biology Volume: 6 Issue: 1 Pages: 1191-1191
  • DOI: 10.1038/s42003-023-05562-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wnt activation-induced disturbance of cell competition causes diffuse invasion of transformed cells through upregulation of NF-κB-mediated MMP21 (2023)
  • Author(s): Nakai, K., Lin, H., Yamano, S., Tanaka, S., Kitamoto, S., Sakuma, K., Kurauchi, J., Akter, E., Konno, M., Koseki, J., Takahashi, H., Yokoyama, H., Shiraki, Y., Enomoto, A., Abe, S., Hayakawa, Y., Ushiku, T., Mutoh, M., Fujita, Y. and Kon, S.
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 7048-7048
  • DOI: 10.1038/s41467-023-42774-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir (2023)
  • Author(s): Torii Shiho、Kim Kwang Su、Koseki Jun、Suzuki Rigel、Iwanami Shoya、Fujita Yasuhisa、Jeong Yong Dam、Ito Jumpei、Asakura Hiroyuki、Nagashima Mami、Sadamasu Kenji、Yoshimura Kazuhisa、Sato Kei、Matsuura Yoshiharu、Shimamura Teppei、Iwami Shingo、Fukuhara Takasuke、The Genotype to Phenotype Japan (G2P-Japan) Consortium
  • Journal Title: PLOS Pathogens Volume: 19 Issue: 3 Pages: e1011231-e1011231
  • DOI: 10.1371/journal.ppat.1011231
  • Peer Reviewed / Open Access
• [Journal Article] Bayesian statistical method for detecting structural and topological diversity in polymorphic proteins (2022)
  • Author(s): Hayashi Shuto、Koseki Jun、Shimamura Teppei
  • Journal Title: Computational and Structural Biotechnology Journal Volume: 20 Pages: 6519-6525
  • DOI: 10.1016/j.csbj.2022.11.038
  • Peer Reviewed / Open Access
• [Journal Article] Theoretical Computational Analysis Predicts Interaction Changes Due to Differences of a Single Molecule in DNA (2022)
  • Author(s): Koseki Jun、Hirose Haruka、Konno Masamitsu、Shimamura Teppei
  • Journal Title: Applied Sciences Volume: 13 Issue: 1 Pages: 510-510
  • DOI: 10.3390/app13010510
  • Peer Reviewed / Open Access
• [Presentation] Development of the Cryptic Site searching method with Mixed-solvent molecular dynamics and Topological data analyses methods (2024)
  • Author(s): Jun Koseki, Chie Motono, Keisuke Yanagisawa, Genki Kudo, Ryunosuke Yoshino, Takatsugu Hirokawa, Kenichiro Imai
  • Organizer: 1st Asia & Pacific Bioinformatics Joint Conference
  • Int'l Joint Research
• [Presentation] Development of the Cryptic Site searching method with Mixed-solvent molecular dynamics and Topological data analyses methods (2024)
  • Author(s): Jun Koseki, Chie Motono, Keisuke Yanagisawa, Genki Kudo, Ryunosuke Yoshino, Takatsugu Hirokawa, Kenichiro Imai
  • Organizer: CBI学会2024年大会
• [Presentation] アミノ酸変異による抗ウイルス薬の薬剤耐性要因解析 (2023)
  • Author(s): 小関 準
  • Organizer: 第 5 回がんと代謝研究会・若手の会
• [Presentation] Analysis of Antiviral Drug Resistance Caused by Amino Acid Mutations (2023)
  • Author(s): J. Koseki, S. Hayashi, S. Torii, S. Iwami, T. Fukuhara, T. Shimamura
  • Organizer: 6th Workshop on Virus Dynamics
  • Int'l Joint Research
• [Presentation] アミノ酸変異による抗ウイルス薬の薬剤耐性要因解析 (2022)
  • Author(s): 小関 準, 林 周斗, 小嶋 泰弘, 廣瀨 遥香, 岩見 真吾, 福原 崇介, 島村 徹平
  • Organizer: 第16回分子科学討論会2022