Histone proteins are collectively mutated at similar frequencies to major oncogenic drivers, yet only a small fraction of these disease-associated oncohistone mutations occur at canonical sites of post-translational modification. I’m working to chart the largely unknown mechanisms driving these oncohistone mutations. Focusing on transient protein–protein interactions, I recently showed that changes to the nucleosome core domain previously thought to play purely a passive structural role can complete rewire genomic functions like transcription by directing recruitment of elongation complex components (Harvey et al., Cell Reports, 2025). By probing these dynamic, nucleosome-centered interactions rather than treating the histone core as a passive substrate, I am expanding on this discovery to uncover the regulatory logic of the nucleosome: the set of biochemical properties and their context dependence that shape the regulatory network centered on nucleosomes, and how this links to its ultimate function. Using these insights, I aim to design the next generation of therapeutics tackling this important class of oncogenic driver mutation to address this challenge epigenetic context.