Reorganization of H3K9me2-modified chromatin regions during mouse embryonic development

The three-dimensional organization of chromatin in the nucleus is critical in regulating gene expression. There are two classes of large genomic regions demarcated by the repressive chromatin modification histone H3 lysine 9 dimethyl (H3K9me2) and enriched at the nuclear periphery: lamina-associated domains (LADs); and H3K9me2-only domains (KODs) which have minimal lamina contact and are highly enriched for transcriptional enhancers. LADs have been studied in multiple cell types. In contrast, KODs have been characterized only in pluripotent cells and it remains to be determined whether they are fixed or rearrange according to cell type. Analysis of KODs from various embryonic mouse tissues revealed that KODs adopt cell type-specific configurations that correlate with changes in lineage-specific enhancer activity. Within KODs, local cell type-specific depletion of H3K9me2 was enriched for H3K27ac peaks at active lineage-specific enhancers. KODs were also enriched across ultra-long regulatory regions suggesting a role for KODs in long-range gene regulation. These results suggest that KODs are cell-type specific and maintain cell type-specific enhancers in a repressed state to allow for tissue- and stage-specific gene activation.