DNA sequence-dependent formation of heterochromatin nanodomains

• Published in: Nature communications Vol. 13; no. 1; p. 1861
• Main Authors: Thorn, Graeme J., Clarkson, Christopher T., Rademacher, Anne, Mamayusupova, Hulkar, Schotta, Gunnar, Rippe, Karsten, Teif, Vladimir B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 45/15; 631/208/176/2016; 631/208/177; 631/208/200; 631/337/100/2285; 639/766/747; ADNP protein; Amino acid sequence; Animals; Base Sequence; Binding sites; Cell differentiation; Chromatin; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone - metabolism; Computer applications; Deoxyribonucleic acid; Differentiation (biology); DNA; Embryo cells; Epigenetics; Gene mapping; Gene sequencing; Genomes; Heterochromatin; Heterochromatin - genetics; Histone H3; Histones; Histones - genetics; Histones - metabolism; Homeodomain Proteins - genetics; Humanities and Social Sciences; Lysine; Methylation; Mice; multidisciplinary; Nerve Tissue Proteins - metabolism; Nucleation; Nucleosomes; Nucleosomes - genetics; Nucleotide sequence; Nucleotides; Pax3 protein; Proteins; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29360-y

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. The ability to predict epigenetic regulation is an important challenge in biology. Here the authors describe heterochromatin nanodomains (HNDs) and compare four different types of H3K9me2/3-marked HNDs in mouse embryonic stem cells. They further develop a computational framework to predict genome-wide HND maps from DNA sequence and protein concentrations, at single-nucleotide resolution.