报告摘要： The three-dimensional genome organization lays the foundation for biological processes involving gene expression and epigenetic regulation. Nevertheless, it is unclear how the genome is structured and regulated at the molecular level. There is a heated debate over the existence of chromatin fibril structure and its regulation by multiple epigenetic regulators. Controversy also remains on the solid or liquid properties of chromatin subject to different environmental conditions. Recent computational advances have enabled direct simulations of biomolecules to reveal their structural mechanisms. However, the large size of chromatin molecules poses a significant challenge to fully sample their functional motions. Here, building upon our recently developed near-atomistic chromatin model, we integrated multiple computational chemistry techniques to examine the structural details of large chromatin systems. Our study of a tetranucleosome, the fundamental unit of chromatin, captures multiple irregular chromatin structures that emerge as intermediates of two chromatin folding pathways. Our further study of a dodecameric nucleosomal array quantitatively reproduces the force-extension curve measured by magnetic tweezers. The simulation also reveals a more complicated folding landscape of chromatin under tension than a stacked-unstacked two-state transition. Additional simulations of multiple poly-nucleosome arrays reveal a stable interdigitated configuration, thereby suggesting a mechanism initiating the sol-gel transition of chromatin. Finally, we show that Polycomb repressive complex 2 (PRC2), a critical epigenetic modification enzyme, can cooperatively loop DNA via allosteric communication and bridge non-adjacent nucleosomes to spread histone modifications. Our work reconciles the stability of different chromatin conformations under in vitro and in vivo environments and uncovers mechanistic insights on the impact of epigenetic regulators on genome organization.
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