Long-term maintenance of H3K27me3 in postmitotic neurons is dispensable for gene expression regulation [ATAC-seq]

Neuronal maturation is associated with extensive changes in gene expression and 3D chromatin architecture. However, the molecular mechanisms that control the epigenetic landscape in terminally differentiated neurons are poorly understood. Here, we show that maturing neurons undergo a striking increase in the levels of the repressive histone modification H3K27me3 broadly across the genome. Using mice with a conditional deletion in the catalytic domain of EZH1, the primary H3K27 methyltransferase in postmitotic neurons, we show that H3K27me3 maintenance depends on EZH1. Strikingly, an almost complete loss of H3K27me3 in postmitotic neurons induces minimal changes in gene expression and chromatin accessibility at 7 months of age. The amino acid composition of EZH1 suggests reduced sensitivity to H3K36 methylation, resulting in distinct activities of EZH1 and EZH2 in different chromatin contexts. Together, our results show that a postmitotic switch from EZH2 to EZH1 establishes novel chromatin domains in neurons with a minimal role in transcriptional maintenance.