Abstract

Three-dimensional chromatin organization lays the foundation for biological processes involving gene expression and epigenetic regulation. Nevertheless, it is unclear how chromatin is structured at the fundamental level. There is a heated debate over the existence of chromatin fibril structure and its response to environmental perturbations. Controversy also remains on the solid or liquid properties of chromatin subject to different experimental conditions. Here, building upon our recently implemented near-atomistic chromatin model, we leverage computational advances to study structural details of large chromatin systems. Our study with a tetranucleosome, the fundamental unit of chromatin, captures multiple irregular chromatin structures that emerge as intermediates of two chromatin folding pathways. Our further study with a dodecameric nucleosomal array repro- duces the force-extension curve measured by magnetic tweezers. The simulation also reveals a more complicated folding landscape of chromatin under tension than a two-state transition: Whereas the shearing motion of compact chromatin under lower tension constitutes the “linear” response regime, a mixture of trinucleosome and tetranucleosome clutches appears as tension increases, leading to an extended nucleosomal array represented as the “plateau” regime on the force-extension curve. Additional simulations with multiple chromatins reveal a stable interdigitated configuration, thereby suggesting a mechanism initiating the sol-gel transition of chromatin. Our integrated work demonstrates the usefulness of the near-atomistic model in reconciling the stability of different chromatin conformations under in vitro and in vivo environments and revealing mechanistic insights underpin- ning genome organization.