# The physical chemistry of interphase loop extrusion

## TL;DR

The paper explains how cohesin proteins organize chromosomes through a process called loop extrusion, using a new model that connects molecular activity to genome structure.

## Contribution

A chemical-reaction network model is introduced to explain cohesin-regulated loop extrusion from first principles.

## Key findings

- Cohesin undergoes bursty loop extrusion with alternating active and inactive states.
- Rapid regulator exchange controls extrusion dynamics over much longer timescales.
- The bursty extrusion model links cellular stoichiometry to genome folding.

## Abstract

Cohesin drives genome organization via loop extrusion, orchestrated by the dynamic exchange of multiple essential accessory proteins. Although these regulators bind the core cohesin complex only transiently, their disruption can dramatically alter loop-extrusion dynamics and chromosome morphology. Still, a quantitative theory of cohesin regulation and its interplay with genome folding is still elusive. Here, we derive a chemical-reaction network model of loop-extrusion regulation from first principles that is fully specified by available in vivo measurements. This “bursty extrusion model” untangles the distinct roles of regulators, whose exchange coincides with intermittent periods of motor activity. By incorporating bursty extrusion in polymer simulations, we reveal how variations in regulatory protein abundance can alter chromatin architecture across length and timescales. Our results are corroborated by in vivo and in vitro observations, bridging the gap between cohesin-regulator dynamics at the molecular scale and their genome-wide consequences on chromosome organization.

•Chemical-reaction network model explicitly describes cohesin-regulator functions•Cohesin undergoes bursty loop extrusion with alternating active and inactive states•Rapid regulator exchange controls extrusion dynamics over much longer timescales•Bursty extrusion model quantitatively relates cellular stoichiometry and genome folding

Chemical-reaction network model explicitly describes cohesin-regulator functions

Cohesin undergoes bursty loop extrusion with alternating active and inactive states

Rapid regulator exchange controls extrusion dynamics over much longer timescales

Bursty extrusion model quantitatively relates cellular stoichiometry and genome folding

Tortora and Fudenberg derive a chemical-reaction network model explaining how cohesin regulators control loop extrusion from first principles. Experimental data uniquely support a “bursty extrusion” mechanism, where cohesins alternate between active and inactive phases during cycles of regulator exchange. Predictions of the bursty extrusion model are validated by microscopy and Hi-C, bridging molecular-scale cohesin dynamics with genome-wide structure.