DNA sequence-dependent formation of heterochromatin nanodomains

The mammalian epigenome contains thousands of heterochromatin nanodomains (HNDs) marked by di- and trimethylation of histone H3 at lysine 9 (H3K9me2/3), which have a typical size of 3–10 nucleosomes. However, what governs HND location and extension is only partly understood. Here, we address this issue by introducing the chromatin hierarchical lattice framework (ChromHL) that predicts chromatin state patterns with single-nucleotide resolution. ChromHL is applied to analyse four HND types in mouse embryonic stem cells that are defined by histone methylases SUV39H1/2 or GLP, transcription factor ADNP or chromatin remodeller ATRX. We find that HND patterns can be computed from PAX3/9, ADNP and LINE1 sequence motifs as nucleation sites and boundaries that are determined by DNA sequence (e.g. CTCF binding sites), cooperative interactions between nucleosomes as well as nucleosome-HP1 interactions. Thus, ChromHL rationalizes how patterns of H3K9me2/3 are established and changed via the activity of protein factors in processes like cell differentiation.