Understanding the role of chromatin accessibility and compaction on loop extrusion dynamics

Abstract

Loop extrusion by SMC complexes is a fundamental mechanism regulating the three-dimensional genome organization, but how these molecular motors navigate through the crowded, nucleosome-covered chromatin fiber remains an open question. Here, we develop a stochastic biophysical model of loop extrusion that explicitly couples motor stepping dynamics to chromatin accessibility and compaction. First, we systematically analyze the role of accessibility on its dynamics across homogeneous, periodic, and random roadblock positioning along chromatin. This comprehensive analysis reveals distinct dynamic regimes: phase-dependent kinetics in periodic arrays where motor step size aligns with obstacle spacing, and anomalous sub-linear progression in disordered environments due to rare but long-lived trapping events. Then, we contextualize our framework to nucleosome-like arrays. Our simulations reveal a non-intuitive dual role for nucleosomes: while they hinder extruder progression by blocking access to linker DNA, their high compaction packs more base pairs per physical distance, enabling larger genomic displacements per step. Strikingly, the resulting base-pair extrusion speed displays a non-monotonic dependence on nucleosome spacing, reaching a maximum at intermediate linker lengths (10-70 bp) that can exceed the speed on naked DNA. Finally, in support of this mechanism, analysis of yeast genomic data shows that a higher nucleosome occupancy between cohesin-associated regions correlates with stronger contact enrichment, consistent with compaction-enhanced extrusion efficiency in vivo. These findings establish chromatin architecture as a tunable regulator of loop extrusion, explaining the comparable speeds observed in vitro and in vivo and providing a quantitative framework for understanding how genome organization emerges from the interplay between motor kinetics and chromatin structure.