A Molecular View\ninto the Structure and Dynamics of\nPhase-Separated Chromatin

The organization\nof chromatin is critical for gene expression,\nyet the underlying mechanisms responsible for this organization remain\nunclear. Recent work has suggested that phase separation might play\nan important role in chromatin organization, yet the molecular forces\nthat drive chromatin phase separation are poorly understood. In this\nwork we interrogate a molecular model of chromatin to quantify the\ndriving forces and thermodynamics of chromatin phase separation. By\nleveraging a multiscale approach, our molecular model is able to reproduce\nchromatin’s chemical and structural details at the level of\na few nanometers, yet remain efficient enough to simulate chromatin\nphase separation across 100 nm length scales. We first demonstrate\nthat our model can reproduce key experiments of phase separating nucleosomal\narrays, and then apply our model to quantify the interactions that\ndrive their formation into chromatin condensates with either liquid-\nor solid-like material properties. We next use our model to characterize\nthe molecular structure within chromatin condensates and find that\nthis structure is irregularly ordered and is inconsistent with existing\n30 nm fiber models. Lastly we examine how post-translational modifications\ncan modulate chromatin phase separation and how the acetylation of\nchromatin can lead to chromatin decompaction while still preserving\nphase separation. Taken together, our work provides a molecular view\ninto the structure and dynamics of phase-separated chromatin and provides\nnew insights into how phase separation might manifest in the nucleus\nof living cells.