Reviewer #2 (Public review): Acetylation of H3K115 is detected associated with fragile nucleosomes at CpG island promoters and active regulatory sites

Acetylation of lysine residues in the tail domain of histone H3 is well characterized, but lysine residues in the histone globular domain are also acetylated. Histone modifications in globular domain have regulatory potential because of their impact on nucleosome stability but remain poorly characterized. In this study we report the genome-wide distribution of acetylated H3 lysine 115 (H3K115ac), a residue on the lateral surface at the nucleosome dyad, using chromatin immunoprecipitation. In mouse embryonic stem cells, we find that detectable H3K115ac is enriched at the transcription start site of active CpG island promoters, but also at polycomb repressed promoters prior to their subsequent activation during differentiation. By contrast, at enhancers H3K115ac enrichment is dynamic, changing in line with gene activation and chromatin accessibility during differentiation. Most strikingly, we show that H3K115ac is detected as enriched on “fragile” nucleosomes within nucleosome depleted regions at promoters, and active enhancers where it coincides with transcription factor binding, and at CTCF bound sites. These unique features suggest that H3K115ac correlates with, and could contribute, to nucleosome destabilization and that it might be a valuable marker for identifying functionally important regulatory elements in mammalian genomes.