Investigating human chromosome organization by whole-genome simulations.

Abstract

Both theoreticians and experimentalists have been dedicating significant effort to studying chromosome organization and its relation to gene expression and regulation. Many experimental procedures were designed, such as Hi-C or ChIA-PET, to capture structural information of chromosomes. Several theoretical models were proposed to understand the principles underlying chromosome compartmentalization. MiChroM is a model that describes the compartmentalization behavior of interphase chromosomes. Compared to experimental data, the agreement of the in silico contact maps suggested that phase separation of A/B compartments is a key feature determining the structure of individual chromosomes. In this work, we use the Open-MiChroM software to simulate the 46 chromosomes of a GM12878 human cell at 50 kb resolution, seeking to understand whether the nuclear organization of the whole genome would rely on the same principles observed for the organization of a single chromosome. The ensemble of structures generated by our simulations captures chromosome organization within territories and phase separation of chromatin compartments. Inside a chromosome territory, active chromatin localizes preferentially in the periphery, while inactive chromatin lies on the inside. The intra-chromosomal contact maps and the shape metrics of each territory are consistent with experimental data. The resulting genome architecture resembles the inverted nucleus configuration, with active chromatin towards the periphery. In the interface between chromosomes, we also observe phase separation of compartments. However, the inter-chromosomal maps present higher contact probabilities for heterochromatin loci when compared to the experimental data. These results suggest that the interactions of chromatin with other nuclear features like the lamina greatly influences inter-chromosomal interactions while also affecting the overall positioning of chromosomes in the nucleus.