Daniel Jost

(Micro)phase-separation in nucleo: formation and dynamics of heterochromatin compartments

The spatial segregation of heterochromatin into distinct, membrane-less nuclear compartments involves the binding of Heterochromatin Protein 1 (HP1) to H3K9me2/3-rich genomic regions. While HP1 exhibits liquid–liquid phase separation properties in vitro, its mechanistic impact on the structure and dynamics of heterochromatin condensate formation in vivo remains largely unresolved. I will present our recent work on modeling the mutual coupling between self-interacting HP1-like molecules and the chromatin polymer. In particular, how the specific affinity of HP1 for H3K9me2/3 loci facilitates coacervation in nucleo and promotes the formation of stable condensates at HP1 levels far below the concentration required to observe phase separation in vitro and how the dynamical cross talk between HP1 and the viscoelastic chromatin scaffold also leads to anomalously slow equilibration kinetics. Finally, I will show how  he morphology of these complex coacervates is further found to be governed by the dynamic establishment of the underlying H3K9me2/3 landscape, which may drive their increasingly abnormal, aspherical shapes during cell development, consistently with 4D microscopy measurements of HP1 condensate formation in live Drosophila embryos performed in collaboration with the Karpen lab.