Interaction energy scales intrinsic to the structural ensemble of chromosomes

Knowledge-based or statistical potential has been successfully used to predict various aspects of folding of proteins and RNA. Here we extend the idea and calculate the statistical potential (SP) between various locus types in order to predict the organization of chromosomes. We estimated the SPs for the pair interactions between loci of binary types (namely, A-A, A-B, or B-B interactions) within a given interphase chromosome from the corresponding contact frequency data in Hi-C experiments. Using the inferred SP values for the energetic parameters in the Chromosome Copolymer Model (CCM), we simulated the structural ensembles for chromosomes 2 and 21 in IMR90 cell, which exhibit the feature of A/B compartments as a result of the phase separation between A and B loci. The interaction scales based on the SPs produce good agreement between the simulated structures and the super-resolution imaging results. At sufficiently high resolution, the SP-based CCM simulations, incorporated with CTCF loop anchors, reveal topologically associating domains (TADs). Each individual chromosome shows different SP values depending on its size and epigenetic sequence as well as the cell type. Our theoretical scheme, which is simple but general, can be applied to many different kinds of experimental data to address the effective chromosome interaction energy scales that govern the underlying structural ensemble.