Researchers have achieved the most detailed imaging yet of chromatin condensates, revealing how DNA fibers fold and interact within these droplet-like structures. The findings link molecular arrangements to the overall behavior of these condensates in cells. This work builds on earlier discoveries about DNA packing mechanisms.
Every human cell packs about six feet of DNA into a nucleus roughly one-tenth the width of a human hair, while keeping it accessible for vital functions. DNA wraps around proteins to create nucleosomes, which link like beads on a string and fold into chromatin fibers. These fibers compact further to fit inside the nucleus.
In 2019, HHMI Investigator Michael Rosen and his team at UT Southwestern Medical Center showed that lab-made nucleosomes form membrane-less droplets through phase separation, akin to oil droplets in water. They proposed this mirrors chromatin condensation in living cells. Chromatin condensates consist of hundreds of thousands of rapidly moving molecules that exhibit collective properties influencing their formation and traits.
To probe deeper, Rosen collaborated with HHMI Investigator Elizabeth Villa at the University of California, San Diego; Rosana Collepardo-Guevara at the University of Cambridge; and Zhiheng Yu at HHMI's Janelia Research Campus. Using cutting-edge imaging at Janelia, they visualized the arrangement of chromatin fibers and nucleosomes inside synthetic condensates. The same techniques examined chromatin in real cells.
Integrating these images with computer simulations and light microscopy, the team found that linker DNA length between nucleosomes affects fiber interactions and the internal network of condensates. This explains variations in phase separation ease and material properties among chromatin types. Synthetic condensates closely mimic cellular compacted chromatin.
"The work has allowed us to tie the structures of individual molecules to macroscopic properties of their condensates, really for the first time," Rosen says. "I'm certain that we're only at the tip of the iceberg -- that we and others will come up with even better ways of developing those structure-function relationships at the meso (intermediate) scale."
The research extends to other biomolecular condensates involved in gene regulation and stress responses. Disrupted condensation may contribute to diseases like neurodegenerative disorders and cancer. "By doing this research, we will better understand how abnormal condensation could lead to different diseases and, potentially, that could help us develop a new generation of therapeutics," notes lead author Huabin Zhou, a postdoctoral scientist in the Rosen Lab.
The study appears in Science (2025; 390 (6777); DOI: 10.1126/science.adv6588).