Topological and nontopological mechanisms of loop formation in chromosomes: Effects on the contact probability.

Chromosomes are crumpled polymer chains further folded into a sequence of stochastic loops via loop extrusion. While extrusion has been verified experimentally, the particular means by which the extruding complexes bind DNA polymer remains controversial. Here we analyze the behavior of the contact probability function for a crumpled polymer with loops for the two possible modes of cohesin binding, topological and nontopological mechanisms. As we show, in the nontopological model the chain with loops resembles a comb-like polymer that can be solved analytically using the quenched disorder approach. In contrast, in the topological binding case the loop constraints are statistically coupled due to long-range correlations present in a nonideal chain, which can be described by the perturbation theory in the limit of small loop densities. As we show, the quantitative effect of loops on a crumpled chain in the case of topological binding should be stronger, which is translated into a larger amplitude of the log-derivative of the contact probability. Our results highlight a physically different organization of a crumpled chain with loops by the two mechanisms of loop formation.

Crumpled polymer with loops recapitulates key features of chromosome organization.

Chromosomes are exceedingly long topologically-constrained polymers compacted in a cell nucleus. We recently suggested that chromosomes are organized into loops by an active process of loop extrusion. Yet loops remain elusive to direct observations in living cells; detection and characterization of myriads of such loops is a major challenge. The lack of a tractable physical model of a polymer folded into loops limits our ability to interpret experimental data and detect loops. Here, we introduce a new physical model - a polymer folded into a sequence of loops, and solve it analytically. Our model and a simple geometrical argument show how loops affect statistics of contacts in a polymer across different scales, explaining universally observed shapes of the contact probability. Moreover, we reveal that folding into loops reduces the density of topological entanglements, a novel phenomenon we refer as "the dilution of entanglements". Supported by simulations this finding suggests that up to ~ 1 - 2Mb chromosomes with loops are not topologically constrained, yet become crumpled at larger scales. Our theoretical framework allows inference of loop characteristics, draws a new picture of chromosome organization, and shows how folding into loops affects topological properties of crumpled polymers.