How enzymatic activity is involved in chromatin organization

TL;DR

This study models how Topoisomerase-II enzyme activity influences chromatin's spatial organization, revealing its role in phase separation and structural differentiation of chromatin regions through computational and theoretical approaches.

Contribution

It introduces a mechanistic polymer physics model of Topoisomerase-II's role in chromatin organization, demonstrating enzyme-driven phase separation and structural features.

Findings

Topoisomerase-II induces phase separation of chromatin into distinct regions.

Enzymatic activity causes euchromatic regions to cross and organize into wall-like structures.

Phase separation features persist even with non-localized enzyme action.

Abstract

Spatial organization of chromatin plays a critical role in genome regulation. Various types of affinity mediators and enzymes have been attributed to regulate spatial organization of chromatin from a thermodynamics perspective. However, at the mechanistic level, enzymes act in their unique ways. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate its role on interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu- and heterochromatic regions with a characteristic wall-like organization of the euchromatic regions. Exploiting a mean-field framework, we argue that the ability of the euchromatic regions crossing each other due to enzymatic activity of Topoisomerase-II induces this phase separation. Motivated from a recent experimental observation on different structural states of the eu- and the heterochromatic units, we further extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survives there. The existence of these characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization, and points out the importance of further experiments along this line.