Highlights d HP1 has only a weak capacity to form droplets in living cells d Size, accessibility, and compaction of heterochromatin foci are independent of HP1 d Heterochromatin compaction is ''digital'' and can toggle between two distinct states d Methodological framework to assess hallmarks of phase separation in living cells
The cell establishes heritable patterns of active and silenced chromatin via interacting factors
that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we
have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts.
We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in
living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2
demarcate the PCH state. From the experimental data, we developed a predictive mathematical model
that explains how chromatin-bound SUV39H1/2 complexes act as nucleation sites and propagate a
spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin
dynamics. This “nucleation and looping” mechanism is particularly robust toward
transient perturbations and stably maintains the PCH state. These features make it an attractive
model for establishing functional epigenetic domains throughout the genome based on the localized
immobilization of chromatin-modifying enzymes.
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