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HP1-driven phase separation recapitulates the thermodynamics and kinetics of heterochromatin condensate formation.
Proc Natl Acad Sci U S A, 120(33):e2211855120.
The spatial segregation of pericentromeric heterochromatin (PCH) into distinct,membrane-less nuclear compartments involves the binding of HeterochromatinProtein 1 (HP1) to H3K9me2/3-rich genomic regions. While HP1 exhibitsliquid-liquid phase separation properties in vitro, its mechanistic impact on thestructure and dynamics of PCH condensate formation in vivo remains largelyunresolved. Here, using a minimal theoretical framework, we systematicallyinvestigate the mutual coupling between self-interacting HP1-like molecules andthe chromatin polymer. We reveal that the specific affinity of HP1 for H3K9me2/3loci facilitates coacervation in nucleo and promotes the formation of stable PCHcondensates at HP1 levels far below the concentration required to observe phaseseparation in purified protein assays in vitro. These heterotypic HP1-chromatininteractions give rise to a strong dependence of the nucleoplasmic HP1 density onHP1-H3K9me2/3 stoichiometry, consistent with the thermodynamics of multicomponentphase separation. The dynamical cross talk between HP1 and the viscoelasticchromatin scaffold also leads to anomalously slow equilibration kinetics, whichstrongly depend on the genomic distribution of H3K9me2/3 domains and result inthe coexistence of multiple long-lived, microphase-separated PCH compartments.The morphology of these complex coacervates is further found to be governed bythe dynamic establishment of the underlying H3K9me2/3 landscape, which may drivetheir increasingly abnormal, aspherical shapes during cell development. Thesefindings compare favorably to 4D microscopy measurements of HP1 condensateformation in live Drosophila embryos and suggest a general quantitative model ofPCH formation based on the interplay between HP1-based phase separation andchromatin polymer mechanics.
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