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. A clique is a set of genes coregulated
all together as a group. 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.