Establishment of heterochromatin in domain-size-dependent bursts

Abstract

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.

Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells

“…They suggested that the reader-writer-eraser capacity of HMEs may generate positive feedback loops and cooperative effects in the system that are essential to provide stability to the local epigenetic state. Applications of such formalism, contextualized to specific marks at specific loci, have shown that it is fully consistent with many experimental observations (13,14,17,(20)(21)(22)(23)(24). However, quantitative comparisons with experiments are still rare in particular on how epigenetic marks organize around the nucleation sites, which may bring crucial information on the spreading and maintenance mechanisms (15,25).…”

A simulation model of heterochromatin formation at submolecular detail

“…In particular, the study ( Erdel et al., 2020 ) has shown that the HP1 concentration in heterochromatin (of ∼3 μM ( Müller-Ott et al., 2014 )) is well below the half-saturation concentration for in vitro droplet formation of ∼40–45 μM. Moreover, an experimental study by ( Nickels et al., 2021 ) suggests that heterochromatin propagates in sudden bursts at different time intervals with HP1 H3K9me reader responsible for this bursting behavior. In agreement with this recent evidence, our simulations demonstrate that a stable highly condensed chromatin state for kilobase-size chromatin regions can be achieved even at a typical cellular HP1 concentration of 2.65 μM, after broadly varying lag times.…”

A Liquid State Perspective on Dynamics of Chromatin Compartments

“…In conclusion, we would also like to mention mesoscopic models that go beyond a lifetime of a single nucleus in order to probe the dynamics of the establishment of heterochromatin compartments and mechanisms of propagation of "epigenetic memory" through cell divisions Ng et al ( 2018 A recent study employing experiment and mathematical modeling Nickels et al (2021) has looked at the fission yeast cell, which contains nucleation center of heterochromatin CenH. By incrementally varying the meting region size, the mathematical model aided by the experiments has come across a remarkable finding that heterochromatin propagation occurs in an all-or-none fashion, where the entire domains collapse abruptly.…”

“…In conclusion, we would also like to mention mesoscopic models that go beyond a lifetime of a single nucleus in order to probe the dynamics of the establishment of heterochromatin compartments and mechanisms of propagation of “epigenetic memory” through cell divisions Ng et al (2018) ; Feinberg and Irizarry (2010) ; Himeoka and Kaneko (2020) ; Nickels et al (2021) . Mathematical models formulated as kinetic monte carlo Dodd et al (2007) ; Nguyen et al (2021) or agent-based Sneppen and Ringrose (2019) dynamical simulations have been widely used to study the stochastic dynamical interplay of local and global feedback mechanisms of histone methylation and acetylation along the 1D genomic sequence.…”

“…A recent study employing experiment and mathematical modeling Nickels et al (2021) has looked at the fission yeast cell, which contains nucleation center of heterochromatin CenH. By incrementally varying the meting region size, the mathematical model aided by the experiments has come across a remarkable finding that heterochromatin propagation occurs in an all-or-none fashion, where the entire domains collapse abruptly.…”