Force generation by protein-DNA co-condensation

Interactions between liquids and surfaces generate forces 1,2 that are crucial for many processes in biology, physics, and engineering, including the motion of insects on the surface of water 3 , modulation of the material properties of spider silk 4 , and self-assembly of microstructures 5 . Recent studies have shown that cells assemble biomolecular condensates via phase separation 6 . In the nucleus, these condensates are thought to drive transcription 7 , heterochromatin formation 8 , nucleolus assembly 9 , and DNA repair 10 . Here, we show that the interaction between liquid-like condensates and DNA generates forces that might play a role in bringing distant regulatory elements of DNA together, a key step in transcriptional regulation. We combine quantitative microscopy, in vitro reconstitution, optical tweezers, and theory to show that the transcription factor FoxA1 mediates the condensation of a DNA-protein phase via a mesoscopic first- order phase transition. After nucleation, co-condensation forces drive growth of this phase by pulling non-condensed DNA. Altering the tension on the DNA strand enlarges or dissolves the condensates, revealing their mechanosensitive nature. These findings show that DNA condensation mediated by transcription factors could bring distant regions of DNA in close proximity, suggesting that this physical mechanism is a possible general regulatory principle for chromatin organization that may be relevant in vivo .