Abstract The mammalian epigenome contains thousands of heterochromatin nanodomains (HNDs) marked by di- and trimethylation of histone H3 at lysine 9, which have a typical size of 3-10 nucleosomes. However, the (epi)genetic determinants of their location and boundaries are only partly understood. Here, we compare 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. Based on a novel chromatin hierarchical lattice framework termed ChromHL, we are able to predict HND maps with singe-nucleotide resolution. We find that HND nucleation can be rationalized by DNA sequence specific protein binding to PAX3/9, ADNP and LINE1 repeats. Depending on type of microdomains, boundaries are determined either by CTCF binding sites or by nucleosome-nucleosome and nucleosome-HP1 interactions. Our new framework allows predicting how patterns of H3K9me2/3 and other chromatin nanodomains are established and changed in processes such as cell differentiation.

DNA sequence-dependent formation of heterochromatin nanodomains