Cancer-associated histone mutations have been implicated in a variety of mechanisms resulting in abnormal chromosomal structure and function. Although many mutations have well-described oncogenic profiles, their effect on higher order chromatin organization (beyond the individual nucleosome) remains unclear. Here, we analyzed a dataset of over 1200 recurrent histone cancer mutations to identify specific mutations, or physiochemical categories of mutations that are high in prevalence despite evolutionary intolerability and improbability to arise from random mutation. We then systematically explored the effects of these mutations on higher order chromatin structure in the context of a 12-nucleosome array modeled using coarse-grained molecular dynamics. We demonstrate that cancer-associated mutations can have a decompacting effect on chromatin structure. For example, by applying a combination of the mutations H3K4M, H3K27M, and H3K36M, we saw significant chromatin decompaction resulting in a major elevation in DNA accessibility as measured through a transcription factor-based probe. Evidence from our simulations raises the possibility that disruption of higher order chromatin structure could be a missing piece in understanding the oncogenic pathways of cancer-associated histone mutations.
Plate et al. (Sun,) studied this question.