Colocalization of coregulated genes: a steered molecular dynamics study of human chromosome 19

TL;DR

This study uses steered molecular dynamics to demonstrate that most gene pairs on human chromosome 19 can be brought into proximity, supporting the idea that gene coregulation and spatial colocalization are compatible and structurally organized.

Contribution

It introduces a computational strategy to simulate and analyze the spatial organization of chromosomes, revealing the feasibility of gene colocalization in a model of human chromosome 19.

Findings

Most (~80%) gene pairs can be simultaneously colocalized.

Chromosome conformations organize into macrodomains similar to HiC data.

Gene coregulation correlates with spatial proximity in the model.

Abstract

The connection between chromatin nuclear organization and gene activity is vividly illustrated by the observation that transcriptional coregulation of certain genes appears to be directly influenced by their spatial proximity. This fact poses the more general question of whether it is at all feasible that the numerous genes that are coregulated on a given chromosome, especially those at large genomic distances, might become proximate inside the nucleus. This problem is studied here using steered molecular dynamics simulations in order to enforce the colocalization of thousands of knowledge-based gene sequences on a model for the gene-rich human chromosome 19. Remarkably, it is found that most (~80%) gene pairs can be brought simultaneously into contact. This is made possible by the low degree of intra-chromosome entanglement and the large number of cliques in the gene coregulatory network, that is the many groups of genes that are all mutually coregulated. The constrained conformations for the model chromosome 19 are further shown to be organised in spatial macrodomains that are similar to those inferred from recent HiC measurements. The findings indicate that gene coregulation and colocalization are largely compatible and that this relationship can be exploited to draft the overall spatial organization of the chromosome in vivo. The more general validity and implications of these findings could be investigated by applying to other eukaryotic chromosomes the general and transferable computational strategy introduced here.