Spatial and topological organization of DNA chains induced by gene co-localization

TL;DR

This paper presents a thermodynamic model of chromosome organization showing how gene co-localization and transcription factories emerge from physical interactions, revealing phases that enhance gene clustering and co-localization.

Contribution

It introduces a worm-like chain model with interacting sites to explain the formation of transcription foci and topological order in chromosomes, supported by numerical simulations.

Findings

Transcription foci resemble micro-phase separation of interacting sites.

Different topological phases increase local concentration of genes.

Periodic and clustered binding sites improve gene co-localization efficiency.

Abstract

Transcriptional activity has been shown to relate to the organization of chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In particular, highly transcribed genes, RNA polymerases and transcription factors gather into discrete spatial foci called transcription factories. However, the mechanisms underlying the formation of these foci and the resulting topological order of the chromosome remain to be elucidated. Here we consider a thermodynamic framework based on a worm-like chain model of chromosomes where sparse designated sites along the DNA are able to interact whenever they are spatially close-by. This is motivated by recurrent evidence that there exists physical interactions between genes that operate together. Three important results come out of this simple framework. First, the resulting formation of transcription foci can be viewed as a micro-phase separation of the interacting sites from the rest of the DNA. In this respect, a thermodynamic analysis suggests transcription factors to be appropriate candidates for mediating the physical interactions between genes. Next, numerical simulations of the polymer reveal a rich variety of phases that are associated with different topological orderings, each providing a way to increase the local concentrations of the interacting sites. Finally, the numerical results show that both one-dimensional clustering and periodic location of the binding sites along the DNA, which have been observed in several organisms, make the spatial co-localization of multiple families of genes particularly efficient.