Cancer mutations rewire linker histone interaction network and compromise chromatosome stability

Histone H1 is essential for higher-order chromatin organization, stabilizing linker DNA and bridging adjacent nucleosomes. To elucidate how cancer-associated mutations perturb this architectural hub, we constructed a comprehensive H1-centered interaction network by integrating structural and cross-linking mass spectrometry data, encompassing interactions among histones, DNA, and regulatory partners. Mapping cancer-associated mutations onto this network revealed significant enrichment at protein-protein interfaces and post-translational modification sites, implicating disruption of histone modification cross talk and network connectivity. Molecular dynamics simulations further demonstrated that these mutations compromised chromatosome stability through distinct mechanisms: linker DNA-binding mutations induce relatively modest perturbations, whereas the dyad-binding mutation S104F disrupts key hydrogen bond networks and markedly enhances conformational flexibility. Together, our multiscale analysis links network topology with atomic-level dynamics, providing mechanistic insights into how H1 mutations rewire chromatin interactions and destabilize nucleosome architecture, thereby advancing our understanding of oncohistone-driven genome dysregulation.