Force generation by protein\u2013DNA co-condensation

Thomas Quail,Frank Jülicher,Roman Renger,Stefan Golfier,Vasanthanarayan Murugesan,Jan Brugués,Maria Elsner,Keisuke Ishihara

doi:10.1038/s41567-021-01285-1

Abstract

Interactions between liquids and surfaces generate forces1,2 that are crucial for many processes in biology, physics and engineering, including the motion of insects on the surface of water3, modulation of the material properties of spider silk4 and self-assembly of microstructures5. Recent studies have shown that cells assemble biomolecular condensates via phase separation6. In the nucleus, these condensates are thought to drive transcription7, heterochromatin formation8, nucleolus assembly9 and DNA repair10. 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 protein–DNA 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 into close proximity, suggesting that this physical mechanism is a possible general regulatory principle for chromatin organization that may be relevant in vivo.

Highlights

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]
The physical nature of these transcriptional hubs is under debate, though recent studies have proposed that transcriptional hubs can be understood as examples of biomolecular condensates[12]
This suggests that forkhead box protein A1 (FoxA1)–DNA condensates generate forces that can overcome the entropic tension of the non-condensed DNA and buffer its tension

Summary

Introduction

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]. For DNA strands with end-to-end distances greater than approximately 10 μm, FoxA1 generated protein condensates on DNA (Fig. 1c). To quantify FoxA1-mediated DNA condensation, we measured the cross-correlation of FoxA1–DNA intensities as a function of end-to-end distance (Methods, Fig. 1d,e and Extended Data Fig. 3a).

Results

Conclusion