The emerging view is that interactions between regulatory elements and promoters are insulated within extensive self-interacting units termed topologically associated domains (TADs), which are further positioned in the nucleus to spatially segregate active and silent chromatin. Proper targeting of sequences to their respective chromatin environment is necessary for genome stability and gene regulation. We have expanded our high-resolution chromosome paints to better visualize epigenome organization across individual chromosomes and are using this tool to study the regulation of architectural proteins and their effects on nuclear, cellular, and physiological phenotypes.