Epigenome manipulation by chemical catalyst-driven abiotic histone acylation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19326
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Chiba University (2023); The University of Tokyo (2021-2022)
• Principal Investigator: Yamatsugu Kenzo 千葉大学, 大学院薬学研究院, 教授 (30646807)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: 触媒 / ヒストン / 生細胞内反応 / アシル化

Outline of Final Research Achievements

Life emerges from biomolecules such as proteins and the chemical reactions mediated by them. Post-translational modification of proteins is a representative example. The purpose of this research is to manipulate and understand the epigenome of cells by introducing abiotic post-translational modifications, particularly acylation of lysine residues, into histone proteins, which are involved in gene transcription, using chemical catalysts.
We developed an acylation catalyst system with higher activity than conventional ones and succeeded in causing growth inhibition through selective histone acylation and epigenome manipulation of leukemia cells. Furthermore, we developed a new catalyst that activates intracellular acyl-CoA to perform histone acylation, and were able to develop an epigenetic tool that detects the concentration of intracellular acyl-CoA, which changes in response to environmental changes.

Free Research Field

有機化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、遺伝子転写に関与するヒストンタンパク質を対象に、本来生体にはない翻訳後修飾を化学触媒により導入し、細胞のエピゲノムを操作すること、細胞の応答を理解することを目的とする。生きた細胞のヒストンに非天然型の化学修飾を積極的に導入して細胞のエピゲノム状態を操作する例はなく、本研究の成果は、化学触媒によるエピゲノム操作という革新的な生体機能制御法の開発に発展すると考えられ、分子生物学、薬学、医学などの広い生命科学分野に大きな波及効果を持つ。