Study Offers New Perspective on How Phase Separation Contributes to Gene Regulation

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.

Biological functions are precisely controlled by when and where genes are expressed. Gene expression is regulated through multiple mechanisms, including transcription factors and epigenetic regulation. Among these, post-translational modifications (PTMs) of histones, the proteins around which DNA is wrapped, have been extensively studied as a major regulatory mechanism. More recently, liquid–liquid phase separation (LLPS), a phenomenon in which proteins and DNA spontaneously assemble into droplet-like condensates that are distinct from their surroundings, has emerged as another mechanism involved in gene regulation. These condensates are thought to regulate gene expression by concentrating or compartmentalizing specific biomolecules. However, the relationship between histone modifications and LLPS 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.

Background

Many cancers and neurodegenerative diseases, including Alzheimer's disease, are thought to involve 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, which regulates gene expression without altering the DNA sequence, plays a central role in this process. 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), a phenomenon in which proteins and DNA spontaneously assemble into droplet-like condensates within cells, has emerged as another mechanism involved in gene regulation. These condensates are thought to regulate gene expression by concentrating or compartmentalizing specific biomolecules involved in gene activity, and alterations in LLPS have also been implicated in a variety of diseases.