Regulation associated modules reflect 3D genome modularity associated with chromatin activity

The 3D genome has been shown to be organized into modules including topologically associating domains (TADs) and compartments that are primarily defined by spatial contacts from Hi-C. There exists a gap to investigate whether and how the spatial modularity of the chromatin is related to the functional modularity resulting from chromatin activity. Despite histone modifications reflecting chromatin activity, inferring spatial modularity of the genome directly from the histone modification patterns has not been well explored. Here, we report that histone modifications show a modular pattern (referred to as regulation associated modules, RAMs) that reflects spatial chromatin modularity. Enhancer-promoter interactions, loop anchors, super-enhancer clusters and extrachromosomal DNAs (ecDNAs) are found to occur more often within the same RAMs than within the same TADs. Consistently, compared to the TAD boundaries, deletions of RAM boundaries perturb the chromatin structure more severely (may even cause cell death) and somatic variants in cancer samples are more enriched in RAM boundaries. These observations suggest that RAMs reflect a modular organization of the 3D genome at a scale better aligned with chromatin activity, providing a bridge connecting the structural and functional modularity of the genome.