How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes

The 3D organization of chromosomes is crucial for regulating gene expression and cell function. Many experimental and polymer modeling efforts are dedicated to deciphering the mechanistic principles behind chromosome folding. Chromosomes are long and densely packed—topologically constrained—polymers. The main challenges are therefore to develop adequate models and simulation methods to investigate properly the multi spatio-temporal scales of such macromolecules. Here, we proposed a generic strategy to develop efficient coarse-grained models for self-avoiding polymers on a lattice. Accounting accurately for the polymer entanglement length and the volumic density, we show that our simulation scheme not only captures the steady-state structural and dynamical properties of the system but also tracks the same dynamics at different coarse-graining. This strategy allows a strong power-law gain in numerical efficiency and offers a systematic way to define reliable coarse-grained null models for chromosomes and to go beyond the current limitations by studying long chromosomes during an extended time period with good statistics. We use our formalism to investigate in details the time evolution of the 3D organization of chromosome 3R (20 Mbp) in drosophila during one cell cycle (20 hours). We show that a combination of our coarse-graining strategy with a one-parameter block copolymer model integrating epigenomic-driven interactions quantitatively reproduce experimental data at the chromosome-scale and predict that chromatin motion is very dynamic during the cell cycle.Author summary: The chromosome architecture inside cell nuclei plays important roles in regulating cell functions. Many experimental and modeling efforts are dedicated to deciphering the mechanisms controlling such organization. There are proliferations of experimental studies which report the hierarchical structure of chromosomes but how exactly they physically organize in 3D is not fully understood. In modeling, the main challenges are to develop adequate models and simulation methods to investigate correctly these highly dense long polymer chains. Taken into consideration the fundamental physical characteristics of chromosomes, we developed robust and numerically efficient polymer models that enabled us to explore the dynamics of long chromosomes over long time periods with good statistics. We applied this framework to investigate the dynamical folding of chromosome in drosophila. Accounting for the local biochemical information, we were able to reproduce the experimentally-measured contact frequencies between any pairs of genomic loci quantitatively and to track the hierarchical chromosome structure throughout the cell cycle. Our results further support the picture of a very dynamic chromosome organization driven by weak short-range interactions.