TRIM66-HP1γ remodels the chromatin through phase separation.

Abstract

Chromatin contains not only heterochromatin (HC) and euchromatins (EC) but also facultative heterochromatin (fHC), which experience the dynamic remodeling between HCs and ECs by different regulators. The regulation of fHCs involves lots of different cell functions, like genomic stability and gene transcription. Heterochromatin protein 1 (HP1) recognizes methylated H3K9 and reshapes the chromatin into the fHCs through liquid-liquid phase separation (LLPS). Among the three members of the HP1 family, HP1α can condensate by itself and HP1β forms granules with the help of TRIM28, while the HP1γ cannot phase separation alone either and the coordinator is still unclear. So, in this study, we investigated the molecular mechanism of how HP1γ interacts with TRIM66 through PxVxL motif. Based on that, we examined the key regions that controlled the TRIM66-HP1γ co-phase separation behaviors both in vitro and in vivo. Furthermore, we proved that the liquid granules of TRIM66-HP1γ and chromatin highly correlated with H3K9me3 sites, which indicated the relationship with DNA damage response. Finally, combined with our previous study, we proposed the system for how TRIM66 remodeled the chromatin into compressed fHC through the TRIM66-HP1γ-H3K9me3 axis with liquid-liquid phase separation.