Physics-based nucleosome-resolution modeling of epigenetic-driven chromatin domain dynamics

Chromatin spatially organizes the eukaryotic genome to support key cellular processes such as gene regulation, but the interplay between epigenetics, chromatin structure, and function is still poorly understood. We propose a nucleosome-resolution coarse-grained model that captures the essential features of chromatin organization over multiple scales: from nucleosome dynamics to chromatin fiber folding, and liquid-liquid phase separation. The model describes the effects of DNA linker length, histone tail acetylation, linker histone H1, and multibromodomain proteins such as BRD4. It is designed to be experimentally accurate but computationally efficient, allowing the study of 100 kb genomic regions on a timescale of seconds with moderate resources. We apply this model to explore the structure and dynamics of two active loci of mouse embryonic stem cells, Pou5f1 and Sox2, as determined solely by epigenetics. Our simulations reveal that chromatin folds into liquid-like domains characterized by similar histone modifications. These domains are highly dynamic, driving the formation of transient contacts between distant cis-regulatory regions. In silico mutation studies further clarify the roles of individual epigenetic factors. Overall, our physics-based modeling establishes that epigenetic-dependent nucleosome interactions play a key role in shaping the functional organization of genomic loci.