Chromosome-Nuclear Envelope Interactions Have Multiple Effects on Chromosome Folding Dynamics in Simulation

Abstract

It is well recognized that the chromosomes of eukaryotes fold into non-random configurations within the nucleus. In humans and fruit flies, chromosomes likely adopt a particular 3D configuration called the fractal globule (FG) which has multiple biologically significant properties. However, the fractal globule is a metastable state which, over time, transitions to a less biologically favorable state called the equilibrium globule. One of the key questions is how the FG state is stabilized in-vivo? We use simulations to study the effects of chromosome-nuclear envelope (Chr-NE) interactions on the dynamics of the fractal globule within a model of Drosophila melanogaster (fruit fly) interphase chromosomes. The computational model represents chromosomes as self-avoiding walks (SAW) bounded by the nuclear envelope (NE). Model parameters such as nucleus size, chromosome persistence length, and chromosome-nuclear envelope interactions are taken directly from experiment. Several key characteristics of the non-equilibrium FG state are monitored during each simulation's progress: chromosome territories, intra-chromosomal interaction probabilities, loci specific diffusion constants, and presence of the Rabl (polarized) chromosome arrangement. Next, we compare the outcomes of simulations which include or exclude Chr-NE interactions. We find that Chr-NE interactions reinforce the non-equilibrium properties such as chromosome territories, high intra-chromosome interaction probabilities, and the Rabl chromosome arrangement. In addition, Chr-NE interactions affect loci specific and averaged chromosomal diffusion. Based on these results we conclude that the presence of Chr-NE interactions may delay the decay of the biologically relevant fractal globule state in vivo.