Nucleosome-scale structure drives linker histone enrichment in heterochromatin in silico

Linker histones have been recognized as dominant determinants of short-range chromatin structure, causing condensation of a 30-nm fiber in vitro, and have been demonstrated both to have important roles in regulating topologically-associating domain (TAD) structure and to be strongly enriched in heterochromatin. However, studies to-date have found great difficulty elucidating the mechanisms by which linker histones selectively partition into heterochromatin, though it has been postulated that H1 may bind to specific histone PTMs or induce modifications of core histones. In this work we introduce a multi-scale polymer model for chromatin which captures both megabase-scale phase separation and nucleosome-scale physics, explicitly accounting for the effects of both DNA linker length and H1 binding. We demonstrate that phase separation induces changes in nucleosome-scale structure which are sufficient to cause co-precipitation of linker histones in heterochromatin at least as great as the enrichment observed in vivo. Our work demonstrates that specific histone-code recognition is not necessary to induce linker histone enrichment in heterochromatin, and illustrates the potential for mesoscale models to answer key questions in biological systems which are experimentally intractable.