The nuclear periphery is a scaffold for tissue-specific enhancers

Abstract Nuclear architecture influences gene regulation and cell identity by controlling the three-dimensional organization of genes and their distal regulatory sequences, which may be far apart in linear space. The genome is functionally and spatially segregated in the eukaryotic nucleus with transcriptionally active regions in the nuclear interior separated from repressive regions, including those at the nuclear periphery. Here, we describe the identification of a novel type of nuclear peripheral chromatin domain that is enriched for tissue-specific transcriptional enhancers. Like other chromatin at the nuclear periphery, these regions are marked by H3K9me2. But unlike the nuclear peripheral Lamina-Associated Domains (LADs), these novel, enhancer-rich domains have limited Lamin B interaction. We therefore refer to them as H3K9me2-Only Domains (KODs). In mouse embryonic stem cells, KODs are found in Hi-C-defined A compartments and feature relatively accessible chromatin. KODs are characterized by low gene expression and enhancers located in these domains bear the histone marks of an inactive or poised state. These results indicate that KODs organize a subset of inactive, tissue-specific enhancers at the nuclear periphery. We hypothesize that KODs may play a role in facilitating and perhaps constraining the enhancer-promoter interactions underlying spatiotemporal regulation of gene expression programs in differentiation and development.