Discovery of dynamic changes in 3D chromatin architecture through polymer physics model

Abstract

The 3D organisation of the genome provides an intricate relationship between the chromatin architecture and its effects on the functional state of the cell. Recent advances in high-throughput sequencing and chromosome conformation capture technologies elucidated a comprehensive view of chromatin interactions on a genome-wide scale but provides only a 2D representation of how the chromatin is organised inside the cell nucleus. To quantitatively understand the structural alterations and dynamics of chromatin in 3D, we have developed a computational model that not only captures the hierarchical structural organisation but also provides mechanistic insights into the dynamics of spatial rearrangements of chromatin in developing lymphoid lineage cells. From the combination of approaches of polymer physics representing chromatin as a homopolymeric chain and incorporation of the biological information of chromosomal interactions inferred from the Hi-C data, we generated a coarse grained bead-on-a-string polymer model of chromatin to comprehend the mechanisms underlying the differential chromatin architecture. Our study showed that our simulated chromatin structure recapitulates the intrinsic features of chromatin organisation, including the fractal globule nature, compartmentalization, presence of topologically associating domains (TADs), phase separation and spatial preferences of genomic regions in the chromosomal territories. Comparative analyses of these simulated chromatin structures of differentiating B cell stages revealed compartmental switching and changes in the spatial positioning of lineage specific genomic regions. Analysis of the compactness of the switched regions showed insights into their acquired open-closed states for gene regulation and hence governing the cell fate through consequent structural rearrangement. Based on the remarkable performance of our model, we emphasise on its predictive potential by identifying switching of novel regions that demonstrated undergoing structural rearrangement which was subsequently validated through their differential expression patterns in vitro. These results reveal that although the chromatin organisation seems similar in most cell types, it undergoes distinct structural changes for the regulatory role of chromatin in sustaining cell specificity.