Mechanistic basis for the opposing effects of H2A and H2B ubiquitination on nucleosome stability and dynamics

Nucleosome ubiquitination at lysine 119 of histone H2A (H2AK119ub) and lysine 120 of histone H2B (H2BK120ub) are prominent post-translational modifications with opposing roles in chromatin regulation. Although H2AK119ub is associated with transcriptional repression and H2BK120ub with activation, the molecular basis for these contrasting effects has remained unclear. Here, we use microsecond all-atom and millisecond coarse-grained molecular dynamics simulations to reveal how the position of ubiquitin reshapes nucleosome structure and assembly. H2AK119ub rigidifies the histone core by indirectly reinforcing the L1-L1 interface between H2A histones, strengthening both tetramer-dimer and dimer-dimer interactions, and slowing complete nucleosome assembly. In contrast, H2BK120ub disrupts these interfaces, weakens the histone core, and favors partially assembled hexasome and tetrasome states. Both modifications cause dramatic slowdowns in nucleosome folding, with H2BK120ub producing an order-of-magnitude greater effect. These simulations establish clear molecular mechanisms by which site-specific ubiquitination alters nucleosome stability and assembly kinetics. Our findings quantitatively explain how H2A and H2B ubiquitination exert opposing effects on chromatin regulation. This mechanism is directly relevant to the opposing roles of these marks in transcriptional activation and repression, and may represent one way that combinations of histone modifications modulate chromatin function in vivo.