How Chromatin Condensates Organize DNA Inside Cells

Every human cell faces a remarkable challenge: how to fit about six feet of DNA into a nucleus only a fraction of a hair’s width while preserving access to essential genetic information. DNA achieves this by wrapping around proteins to form nucleosomes—bead-like structures joined into strings that coil into compact chromatin fibers tightly packed within the nucleus. Yet until recently, the mechanism behind this higher-level compaction remained unclear. 

In 2019, Michael Rosen and his team at UT Southwestern Medical Center discovered that synthetic nucleosomes can form dense, membrane-less droplets called condensates through a process known as phase separation, similar to how oil droplets appear in water. These structures, believed to mimic chromatin organization in cells, consist of thousands of rapidly moving molecules with unique behaviors that emerge only when the molecules act collectively.

To explore what happens inside these chromatin condensates, Rosen collaborated with 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 advanced cryo-electron microscopy at Janelia, the team captured the most detailed images to date of chromatin fibers and nucleosomes within synthetic condensates and compared them with native chromatin in cells.

By combining high-resolution imaging, computer simulations, and light microscopy, the researchers were able to study how the physical structure of individual molecules influences the formation and material properties of condensates. They found that the length of linker DNA connecting nucleosomes determines how chromatin fibers are arranged and interact, shaping the overall structure and dynamics of the condensate network. These insights explain why some types of chromatin undergo phase separation more readily than others and why condensates vary in their molecular organization. Notably, the team showed that lab-generated condensates share structural similarities with compacted DNA found naturally inside cells.

“The work has allowed us to tie the structures of individual molecules to macroscopic properties of their condensates, really for the first time,” Rosen said. “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.”

Beyond chromatin organization, the findings offer a framework for investigating many other biomolecular condensates that influence gene regulation, stress responses, and disease processes. “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,” said Huabin Zhou, first author on the study published in Science.