Principles of 3D compartmentalization of the human genome

Abstract Chromatin is organized in the nucleus by CTCF loops and compartmental domains, the latter of which contain sequences bound by proteins capable of mediating interactions among themselves. While compartmental domains are one of the most prominent features of genome 3D organization at the chromosome scale, we lack a nuanced understanding of the different types of compartmental domains present in chromosomes and a mechanistic knowledge of the forces responsible for their formation. In this study, we compared different cell types to identify distinct paradigms of compartmental domain formation in human tissues. We identified and quantified compartmental forces correlated with histone modifications characteristic of transcriptional activity as well as previously underappreciated roles for compartmental domains correlated with the presence of H3K9me3, H3K27me3, or none of these histone modifications. We present a simple computer simulation model capable of predicting compartmental organization based on the biochemical characteristics of independent chromatin features. Using this computational model, we show that the underlying forces responsible for compartmental domain formation in human cells are conserved and that the diverse compartmentalization patterns seen across cells are due to differences in chromatin features. We extend these findings to Drosophila to suggest that the same fundamental forces are at work beyond humans. These results offer mechanistic insights into the fundamental forces driving the 3D organization of the genome.