Thermodynamic pathways to genome spatial organization in the cell nucleus

TL;DR

This paper presents a thermodynamic model explaining how the spatial organization of the genome in the nucleus emerges from physical interactions, with simulations showing stable configurations influenced by molecular concentrations and chromatin features.

Contribution

It introduces a novel thermodynamic switch model that quantitatively explains genome organization dynamics based on molecular interactions and chromatin modifications.

Findings

Chromosomes form stable territories and loops through thermodynamic mechanisms.

Nuclear architecture is regulated by soluble mediator concentrations and chromatin attachment sites.

The model links gene regulation strategies to physical genome organization.

Abstract

The architecture of the eukaryotic genome is characterized by a high degree of spatial organization. Chromosomes occupy preferred territories correlated to their state of activity and, yet, displace their genes to interact with remote sites in complex patterns requiring the orchestration of a huge number of DNA loci and molecular regulators. Far from random, this organization serves crucial functional purposes, but its governing principles remain elusive. By computer simulations of a Statistical Mechanics model, we show how architectural patterns spontaneously arise from the physical interaction between soluble binding molecules and chromosomes via collective thermodynamics mechanisms. Chromosomes colocalize, loops and territories form and find their relative positions as stable thermodynamic states. These are selected by "thermodynamic switches" which are regulated by concentrations/affinity of soluble mediators and by number/location of their attachment sites along chromosomes. Our "thermodynamic switch model" of nuclear architecture, thus, explains on quantitative grounds how well known cell strategies of upregulation of DNA binding proteins or modification of chromatin structure can dynamically shape the organization of the nucleus.