Histone H4 acetyl-methyllysine marks accessible chromatin that resists compaction

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.