Neurodevelopmentally Dynamic Regulation of Euchromatin by Polycomb Repressor Complexes

The Polycomb Repressor Complexes (PRCs) play fundamental roles in chromatin regulation, however their neuronal functions remain incompletely understood despite being linked to inherited neurodevelopment disorders. In this study, we map the PRC1 product ubiquitinated histone 2A (H2AK119ub) in the mouse cerebellum, discovering that brain-specific patterns of H2AK119ub appear within both euchromatin and facultative heterochromatin. H2AK119ub undergoes extensive remodeling during neurodevelopment, becoming enriched within active enhancers and simultaneously depleted from heterochromatin. Enhancer-associated H2AK119ub overlapped with active and repressive chromatin loops within neuron-specific gene networks at key neurodevelopmental loci. Furthermore, the PRC2 product H3K27me1 was also neurodevelopmentally remodeled genome-wide within expressed loci to much greater degree than H3K27me3 was in heterochromatin. Hence, dynamic histone modification by PRCs during brain maturation impacts euchromatin more than heterochromatin, with fundamental implications for our understanding of neurodevelopmental gene regulation.