Physical models for chromosome organization to predict multi-contact statistics

Abstract

Whereas pairwise Hi-C methods have taught us much about chromosome organization, new multi-contact 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 non-interacting 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.

HIV integrase compacts viral DNA into biphasic condensates

“…It is interesting to note that this architecture resembles a polymer brush, the model that similarly describes the folding of eukaryotic chromosomes 42 that are orders of magnitude larger and also plays key roles in the organization of prokaryotic genomes. 43 Importantly, we experimentally demonstrate that the center of the rosette and the outer layer of the fully compacted IN-DNA complexes interact differently with the inhibitor CX014442: while the center of the rosette dissolves in an inhibitor concentrationdependent manner, the outer layer of the fully compacted state is not susceptible to the inhibitor in the concentration range probed, irrespective of the order of addition of the inhibitor (Supplementary Fig. S21).…”

Loop-extruders alter bacterial chromosome topology to direct entropic forces for segregation

“…To test our predictions, we construct a simulation scheme for loop-extrusion on a replicating bacterial chromosome, by adapting a previously published algorithm for a single bacterial chromosome [32,33], with system parameters modelled after C. crescentus [38,39,40,41] (SI Appendix). Briefly, the 1D simulations for loop-extrusion are set to track the positions of independently moving replication forks (Fig.…”

A maximum-entropy model to predict 3D structural ensembles of chromatins from pairwise distances: Applications to Interphase Chromosomes and Structural Variants

“…We next asked if the method accounts for higher-order structures, such as three way contacts, discovered in GAM [27,28] and SPRITE experiments [26] and imaging experiments [47] , and predicted by the theory [64,65]. First, we computed the probability of co-localization of loci triplets, π ijk (a) = Pr(r ij < a, r ik < a, r jk < a) where a is the distance threshold for contact formation (r ij < a implies a contact).…”