Chromatin organization by an interplay of loop extrusion and compartmental segregation

TLDR

Human DNA (~2 m) is compacted into a 10‑µm nucleus, and experiments have shown that genome organization consists of compartments of alternating active/inactive regions and compact domains, which are thought to arise from microphase separation and motor‑driven loop extrusion, respectively. The authors aim to integrate these two mechanisms into a polymer model to explain diverse experimental observations in wild‑type and mutant cells. They construct a polymer model that simultaneously incorporates loop extrusion and compartmental segregation to capture the interplay between active and passive forces shaping chromatin. The model offers a framework for interpreting chromosome organization across cellular phenotypes and demonstrates that chromatin behaves as complex active matter governed by phase segregation and loop extrusion.

Abstract

Significance Human DNA is 2 m long and is folded into a 10-μm-sized cellular nucleus. Experiments have revealed two major features of genome organization: Segregation of alternating active and inactive regions into compartments, and formation of compacted local domains. These were hypothesized to be formed by different mechanisms: Compartments can be formed by microphase separation and domains by active, motor-driven, loop extrusion. Here, we integrate these mechanisms into a polymer model and show that their interplay coherently explains diverse experimental data for wild-type and mutant cells. Our results provide a framework for the interpretation of chromosome organization in cellular phenotypes and highlight that chromatin is a complex, active matter shaped by an interplay of phase segregation and loop extrusion.