―Potential Role of the Histone Acetylation Site in Regulating Liquid–Liquid Phase Separation―
Researchers) MIMURA Masahiro Technical Trainee (at the time of the study), ISHIHARA Sayaka Technical Staff, KURITA Ryoji Attached to the Research Department, TOMITA Shunsuke Group Leader, Health and Medical Research Institute, KAMEDA Tomoshi Chief Senior Researcher, Artificial Intelligence Research Center, SHINKAI Yoichi Group Leader, Cellular and Molecular Biotechnology Research Institute
Many cancers and neurodegenerative diseases, including Alzheimer's disease, are thought to be associated with abnormalities in the regulation of gene expression. Therefore, understanding how gene expression is regulated at the molecular level is expected to facilitate the discovery of new therapeutic strategies and drug targets, making this an active area of research worldwide.
Epigenetics plays a central role in this process by regulating gene expression without altering the DNA sequence. One of its major mechanisms involves post-translational modifications (PTMs) of histones, the proteins around which DNA is wrapped. Among these modifications, histone acetylation has been closely associated with cancer and neurodegenerative diseases.
In recent years, liquid–liquid phase separation (LLPS) has emerged as another mechanism involved in gene regulation. LLPS is a phenomenon in which proteins and DNA spontaneously assemble into droplet-like condensates within cells. These condensates are thought to regulate gene expression by concentrating or compartmentalizing specific biomolecules involved in gene activity. Alterations in LLPS have also been implicated in a variety of diseases.
A research team from AIST, the Institute of Science Tokyo, and Ritsumeikan University has demonstrated that the phase behavior of histone–DNA condensates depends on the site of histone acetylation.
Histone modifications and liquid–liquid phase separation (LLPS) are both recognized as important regulators of gene expression. However, the relationship between these mechanisms has remained largely unclear. Dysregulation of these regulatory mechanisms has also been implicated in cancer and neurodegenerative diseases.
The research team has been investigating the molecular mechanisms and biological functions of LLPS involving DNA and proteins. In this study, the researchers focused on histone acetylation and demonstrated that the site of histone H3 acetylation affects the propensity of histone H3 and DNA to form condensates. Their findings show that phase behavior is influenced not only by whether histone acetylation occurs, but also by where it occurs. This study provides new insights into the relationship between histone modifications and LLPS, offering a new perspective on how phase separation contributes to gene regulation. The findings may also provide new avenues for the development of therapeutics and diagnostics targeting aberrant gene expression.
The study was published online in the Journal of the American Chemical Society on May 7, 2026.
Journal: Journal of the American Chemical Society
Title of paper: Proximity of the histone-acetylation site to the termini shapes phase behavior with DNA
Authors: Masahiro Mimura, Hiroka Sugai, Tomoshi Kameda, Ryo Kitahara, Soichiro Kitazawa, Yoichi Shinkai, Sayaka Ishihara, Ryoji Kurita, and Shunsuke Tomita
DOI: https://doi.org/10.1021/jacs.6c02267