Histone tail-DNA condensates show acetylation-dependent viscoelastic coupling to single DNA mechanics

Histone tails encode epigenetic information through post-translational modifications (PTM), facilitating chromatin’s compartmentalization into transcriptionally permissive and repressive domains. Their disordered nature is hypothesized to be crucial for mediating DNA and nucleosomal bridging interactions, which in turn control higher-order chromatin organization. Here, we employ experiments and multiscale simulations to study the phase behavior of nucleosome core particles (NCPs) and interrogate how histone H4-tail acetylation impacts condensate material properties. The NCP condensates show phase separation with an upper critical solution temperature (UCST) in the presence of mono and divalent ions. Acetylation of H4 lysine16 (H4 K16-Ac) reduces the UCST of NCP condensates, suggesting a lowering of phase separation driving force. Nanoscale rheology measurements reveal condensates formed by NCPs, as well as H4-tail DNA complexes, are viscoelastic fluids with dominantly viscous behavior that is weakened by H4 K16-Ac. Atomistic simulation indicates that K16 acetylation enhances homotypic H4 tail-tail interactions at the expense of heterotypic tail-DNA interactions. To map the concomitant mechanical impact of H4 K16-Ac at the single-DNA level, we employed a single molecule mechanosensing (SMM) approach using a dual-trap optical tweezer. Using SMM, we observe that DNA condensation is tail sequence-specific and find that H4 K16-Ac reduces condensation force on a single DNA molecule by ~ 3-fold. Our results establish a direct correlation between the bulk material property and condensation forces at the single molecule level and suggest how molecular mechanics across the single chain to mesoscale can be modulated by PTMs.