Protein-DNA Co-condensation is Prewetting to a Collapsed Polymer

TL;DR

This paper demonstrates how long polymers like chromatin can undergo a prewetting transition when interacting with protein mixtures, leading to coupled phase separation and polymer collapse, which may influence nuclear organization.

Contribution

It introduces a generalized prewetting transition model showing polymer collapse coupled with liquid droplet formation, supported by simulations and mean-field theory.

Findings

Polymer collapse can be stabilized by protein phase separation.

Transitions can be abrupt or continuous depending on conditions.

Changes in protein concentration affect polymer structure.

Abstract

The three-dimensional organization of chromatin is thought to play an important role in controlling gene expression. Specificity in expression is achieved through the interaction of transcription factors and other nuclear proteins with particular sequences of DNA. At unphysiological concentrations many of these nuclear proteins can phase-separate in the absence of DNA, and it has been hypothesized that, in vivo, the thermodynamic forces driving these phases help determine chromosomal organization. However it is unclear how DNA, itself a long polymer subject to configurational transitions, interacts with three-dimensional protein phases. Here we show that a long compressible polymer can be coupled to interacting protein mixtures, leading to a generalized prewetting transition where polymer collapse is coincident with a locally stabilized liquid droplet. We use lattice Monte-Carlo simulations and a mean-field theory to show that these phases can be stable even in regimes where both polymer collapse and coexisting liquid phases are unstable in isolation, and that these new transitions can be either abrupt or continuous. For polymers with internal linear structure we further show that changes in the concentration of bulk components can lead to changes in three-dimensional polymer structure. In the nucleus there are many distinct proteins that interact with many different regions of chromatin, potentially giving rise to many different Prewet phases. The simple systems we consider here highlight chromatin's role as a lower-dimensional surface whose interactions with proteins are required for these novel phases.