A study published in *Nature* (485(7398): 376–380. doi:10.1038/nature11082) identifies topological domains as a pervasive structural feature of mammalian genomes. These domains, defined by large, megabase-sized regions of chromatin interactions, are stable across different cell types and highly conserved between species. The boundaries of these domains are enriched for the insulator binding protein CTCF, housekeeping genes, tRNAs, and SINE retrotransposons, suggesting these factors may play a role in establishing the domain structure. The researchers used Hi-C data from mouse embryonic stem cells (mESCs), human embryonic stem cells (hESCs), and human IMR90 fibroblasts to analyze the 3D organization of the genome. They identified 2,200 topological domains in mESCs, which occupy ~91% of the genome. These domains are characterized by high intra-domain interaction frequencies compared to inter-domain interactions. FISH probes within the same domain are closer in nuclear space than those in different domains, indicating that topological domains reflect spatial organization. The study also found that topological domain boundaries correlate with regions of the genome displaying classical insulator and barrier element activity. These boundaries are enriched for CTCF binding and show a clear segregation of the heterochromatin mark H3K9me3, suggesting that topological domains may "pre-mark" the end points of heterochromatic spreading. The researchers compared topological domains with previously described domain-like structures, including A and B compartments, Lamina-Associated Domains (LADs), replication time zones, and Large Organized Chromatin K9-modification (LOCK) domains. They found that topological domains are related but independent from these structures. The study also investigated the conservation of topological domains across evolution. They found that the majority of boundaries are shared between mouse and human ES cells, suggesting that the domain structure is conserved across species. The researchers identified multiple factors associated with topological boundary regions, including CTCF, housekeeping genes, and SINE elements. These findings suggest that topological domains are a fundamental organizing principle of metazoan genomes.A study published in *Nature* (485(7398): 376–380. doi:10.1038/nature11082) identifies topological domains as a pervasive structural feature of mammalian genomes. These domains, defined by large, megabase-sized regions of chromatin interactions, are stable across different cell types and highly conserved between species. The boundaries of these domains are enriched for the insulator binding protein CTCF, housekeeping genes, tRNAs, and SINE retrotransposons, suggesting these factors may play a role in establishing the domain structure. The researchers used Hi-C data from mouse embryonic stem cells (mESCs), human embryonic stem cells (hESCs), and human IMR90 fibroblasts to analyze the 3D organization of the genome. They identified 2,200 topological domains in mESCs, which occupy ~91% of the genome. These domains are characterized by high intra-domain interaction frequencies compared to inter-domain interactions. FISH probes within the same domain are closer in nuclear space than those in different domains, indicating that topological domains reflect spatial organization. The study also found that topological domain boundaries correlate with regions of the genome displaying classical insulator and barrier element activity. These boundaries are enriched for CTCF binding and show a clear segregation of the heterochromatin mark H3K9me3, suggesting that topological domains may "pre-mark" the end points of heterochromatic spreading. The researchers compared topological domains with previously described domain-like structures, including A and B compartments, Lamina-Associated Domains (LADs), replication time zones, and Large Organized Chromatin K9-modification (LOCK) domains. They found that topological domains are related but independent from these structures. The study also investigated the conservation of topological domains across evolution. They found that the majority of boundaries are shared between mouse and human ES cells, suggesting that the domain structure is conserved across species. The researchers identified multiple factors associated with topological boundary regions, including CTCF, housekeeping genes, and SINE elements. These findings suggest that topological domains are a fundamental organizing principle of metazoan genomes.