Establishment of heterochromatin in domain-size-dependent bursts

Abstract

Significance How repressive heterochromatic states propagate along chromosomes and are subsequently maintained for many cell divisions remain important unanswered questions in biology. Combining mathematical modeling and single-cell measurements, we find that heterochromatin does not propagate in a purely linear manner as often assumed. Rather, sudden transitions can affect large domains globally at once. We suggest this is due to long-range interactions that bring distant nucleosomes close to each other to facilitate their modification. This supports the notion that the compartmentalization of chromatin components within the nucleus and the folding of chromatin into loops dynamically control heterochromatin propagation in three dimensions by bringing nucleosomes and their modifiers into close proximity. Methylation of histone H3K9 is a hallmark of epigenetic silencing in eukaryotes. Nucleosome modifications often rely on positive feedback where enzymes are recruited by modified nucleosomes. A combination of local and global feedbacks has been proposed to account for some dynamic properties of heterochromatin, but the range at which the global feedbacks operate and the exact mode of heterochromatin propagation are not known. We investigated these questions in fission yeast. Guided by mathematical modeling, we incrementally increased the size of the mating-type region and profiled heterochromatin establishment over time. We observed exponential decays in the proportion of cells with active reporters, with rates that decreased with domain size. Establishment periods varied from a few generations in wild type to >200 generations in the longest region examined, and highly correlated silencing of two reporters located outside the nucleation center was observed. On a chromatin level, this indicates that individual regions are silenced in sudden bursts. Mathematical modeling accounts for these bursts if heterochromatic nucleosomes facilitate a deacetylation or methylation reaction at long range, in a distance-independent manner. A likely effector of three-dimensional interactions is the evolutionarily conserved Swi6HP1 H3K9me reader, indicating the bursting behavior might be a general mode of heterochromatin propagation.