Regulatory roles of three-dimensional structures of topologically associating domains

1 Abstract Transcriptional enhancers usually, but not always, regulate genes within the same topologically associating domain (TAD). We hypothesize that this incomplete insulation is due to three-dimensional structures of corresponding chromatin domains in individual cells: Whereas enhancers and genes buried inside the “core” of a domain interact mostly with other regions in the same domain, those on the “surface” can more easily interact with the outside. Here we show that a simple measure, the intra-TAD ratio, can quantify the “coreness” of a region with respect to single-cell domains it belongs. We show that domain surfaces are permissive for high gene expression, and cell type-specific active cis-regulatory elements (CREs), active histone marks, and transcription factor binding sites are enriched on domain surfaces, most strongly in chromatin subcompartments typically considered inactive. These findings suggest a “domain surface CRE” model of gene regulation. We also find that disease-associated non-coding variants are enriched on domain surfaces.