Structural basis for the preservation of a subset of topologically associating domains in interphase chromosomes upon cohesin depletion

Abstract

Compartment formation in interphase chromosomes is a result of spatial segregation between eu- and heterochromatin on a few mega base pairs (Mbp) scale. On the sub-Mbp scales, Topologically Associating Domains (TADs) appear as interacting domains along the diagonal in the Hi-C contact map (CM). Hi-C experiments showed that most of the TADs vanish upon deleting cohesin, while the compartment structure is maintained and is even enhanced. However, closer inspection of the data reveals that a non-negligible fraction of TADs is preserved (P-TADs) after cohesin loss. Imaging experiments show that, at the single-cell level, TAD-like structures are present even without cohesin. To provide a structural basis for these findings, we used polymer simulations to show that certain TADs with epigenetic mismatches across their boundaries survive after depletion of loops. More importantly, the three-dimensional structures show that many of the P-TADs have sharp physical boundaries. Informed by the simulations, we analyzed the Hi-C maps (with and without cohesin) in mouse liver and HCT-116, which affirmed that epigenetic mismatches and physical boundaries (calculated using the 3D structures) explain the origin of the P-TADs. Single-cell structures, calculated from using only the Hi-C map without any parameters, display TAD-like features in the absence of cohesin that are remarkably similar to the findings in imaging experiments, thus providing a cross validation of the computations. Some P-TADs, with physical boundaries, are relevant to the retention of enhancer-promoter/promoter-promoter interactions. Overall, our study shows that preservation of a subset of TADs upon removing cohesin is a robust phenomenon that is valid across multiple cell lines.