Oct4 clusters promote DNA accessibility by enhancing chromatin plasticity

Abstract

Pioneer transcription factors are defined by their ability to engage closed chromatin and render it accessible. Oct4, a master regulator of pluripotency, exemplifies this capacity as it can bind nucleosome-occupied DNA. Yet, how Oct4 reshapes chromatin fibres beyond the scale of a single nucleosome has remained unclear. Here, we harness our near-atomistic coarse-grained chromatin model to dissect how full-length Oct4 interacts with chromatin fibres of varying nucleosomal repeat lengths. We find that Oct4 increases DNA accessibility not by decondensing chromatin, but by driving fibres into compact liquid-like states in which nucleosomes breathe, reorient, exchange neighbours, and transiently expose DNA. Oct4 binds preferentially to linker DNA through its structured POU domains, while its disordered activation domains mediate cluster formation: a three-stage process consisting of nucleation of small clusters, attachment to chromatin via the DNA binding domains, and growth that is amplified when long DNA linkers enable fibre bending and looping. Oct4 clusters deform chromatin and bridge distal DNA segments in a stoichiometry- and linker length-dependent manner, revealing a tunable mechanism for controlling higher-order structure. Together, our results establish how Oct4 exploits multivalency, nucleosome breathing, and chromatin flexibility to reorganise fibres into liquid-like states that reconcile condensation with enhanced accessibility, providing a physical route to overcome the transcription-factor search problem and activate silenced genes during reprogramming.