Abstract
Whereas pairwise Hi-C methods have taught us much about chromosome organization, new multicontact methods, such as single-cell Hi-C, hold promise for identifying higher-order loop structures. The presence of such high-order structure may be revealed by comparing multi-contact data with a theoretical prediction based on pairwise contact information. Here, we develop and compare three polymer-based prediction schemes for chromosomal three-point contact frequencies, based on a noninteracting polymer, a polymer with independent cross-linking, and a polymer with weak pairwise interactions between monomers. First, we test these predictions for two distinct simulation models of bacterial chromosome organization: a data-driven model inferred from a Hi-C map and bottom-up simulations of loop-extruding proteins. We find that the most predictive approximation is indicative of how contacts are primarily formed in a model. We then apply our prediction schemes to previously published super-resolution chromatin tracing data for human IMR90 cells. Strikingly, we find that the best prediction is given by the independent cross-linking approximation. This result is consistent with chromosomal contacts being dominantly caused by weakly interacting loop-extruders. Our work could have implications for developing models of chromosome organization from multi-contact data, and for better identifying higher-order loop structures.
Competing Interest Statement
The authors have declared no competing interest.