Understanding adaptive roles of gene expression noise by manipulating noise and heredity levels

2019 Fiscal Year Final Research Report

• Project/Area Number: 15KT0075
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Constructive Systems Biology
• Research Institution: The University of Tokyo
• Principal Investigator: Wakamoto Yuichi 東京大学, 大学院総合文化研究科, 准教授 (30517884)
• Project Period (FY): 2015-07-10 – 2020-03-31
• Keywords: 遺伝子発現ゆらぎ / パーシスタンス / 薬剤耐性

Outline of Final Research Achievements

The adaptation phenomena of bacterial clonal cell populations include persistence, which occurs on the timescale of several generations, and long-term adaptation that occurs over tens to hundreds of generations. In this research project, we constructed E. coli cell strains with altered statistical properties of expression noise of survival-correlated genes. We then analyzed their drug response in detail using our unique single-cell measurement technology. We also constructed an analytical framework for quantitative evaluation of fitness landscape and selection strength based on the information of cell lineage trees and expression fluctuation. From these experiments, we revealed that multiple survival modes coexist in bacterial persistence and that long-term adaptation to drugs occurs through the remodeling of global gene expression state.

Free Research Field

１細胞生物物理学

Academic Significance and Societal Importance of the Research Achievements

本研究課題の成果により、遺伝子発現のゆらぎの統計的性質が細胞集団の適応応答の関係すること、一方で、長期的に起こる適応応答は、生存関連因子の発現量の大小にほとんど依存せず発生することが明らかになった。これらの結果から、短い時間スケールで起こる適応では局所的な応答が重要な役割を果たす一方、生存細胞の中ではより安定な適応を実現するグローバルな状態変化が長い時間をかけて起こることが明らかになった。また、同一集団内で複数の生存モード、発現状態が観察されたことから、従来の集団計測の限界と１細胞時系列解析の重要性を明らかにした。これらの成果は、細菌の耐性獲得の抑制手法の確立にもつながると考えられる。