The interplay between phase-separation and gene-enhancer communication: a theoretical study

TL;DR

This study uses molecular dynamics simulations to explore how phase separation influences the formation of molecular clusters that facilitate communication between distant gene regulatory elements, revealing conditions that promote such interactions.

Contribution

It introduces a theoretical model demonstrating how phase separation and regulatory site interactions jointly enable enhancer-promoter contacts in chromatin.

Findings

Phase-separated clusters can form under specific molecular conditions.

Regulatory sites can promote or be promoted by phase separation.

Different dynamical regimes facilitate enhancer-promoter interactions.

Abstract

The phase-separation occurring in a system of mutually interacting proteins that can bind on specific sites of a chromatin fiber is here investigated. This is achieved by means of extensive Molecular Dynamics simulations of a simple polymer model which includes regulatory proteins as interacting spherical particles. Our interest is particularly focused on the role played by phase-separation in the formation of molecule aggregates that can join distant regulatory elements, such as gene promoters and enhancers, along the DNA. We find that the overall equilibrium state of the system resulting from the mutual interplay between binding molecules and chromatin can lead, under suitable conditions that depend on molecules concentration, molecule-molecule and molecule-DNA interactions, to the formation of phase-separated molecular clusters allowing robust contacts between regulatory sites. Vice-versa, the presence of regulatory sites can promote the phase-separation process. Different dynamical regimes can generate the enhancer-promoter contact, either by cluster nucleation at binding sites or by bulk spontaneous formation of the mediating cluster to which binding sites are successively attracted. The possibility that such processes can explain experimental live-cell imaging data measuring distances between regulatory sites during time is also discussed.