Reorganization of H3K9me2-modified chromatin regions during mouse embryonic development

Nuclear architecture – the three-dimensional organization of chromatin in the nucleus – is a critical factor in the regulation of gene expression. The repressive histone modification histone H3 lysine 9 dimethyl (H3K9me2) is enriched at the nuclear periphery and demarcates two types of large genomic regions: lamina-associated domains (LADs); and H3K9me2-only domains (KODs) which have minimal contact with the lamina. LADs have been extensively studied and contain repressed lineage-specific genes. KODs, first identified in pluripotent stem cells, were enriched for transcriptional enhancers. By mapping genome-wide H3K9me2-modified and Lamin B1-associated chromatin in developing embryonic mouse cells, we identify cell type-specific configurations of both LADs and KODs. Our analyses reveal that LAD reorganization, which occurs during cell differentiation, correlates with lineage-specific gene expression changes, while KOD reorganization is linked to changes in lineage-specific transcriptional enhancer activity. Interestingly, cell type-specific local depletion of H3K9me2 in KODs was found to correlate with peaks of H3K27ac at active lineage-specific enhancers. We also note that ultra-long regulatory regions are frequently marked by KODs, suggesting a role for KODs in long-range gene regulation. We propose a model in which KODs organize and maintain cell type-specific enhancers in a repressed state to allow for tissue- and stage-specific gene activation. Overall design: Cut&Run profiling H3K9me2 or LaminB in mES, E11.5 heart, or E11.5 forebrain