The spatial organization of the genome is intimately linked to its biological 
function, yet our understanding of higher order genomic structure is coarse, 
fragmented and incomplete. In the nucleus of eukaryotic cells, interphase 
chromosomes occupy distinct chromosome territories, and numerous models have 
been proposed for how chromosomes fold within chromosome territories. These 
models, however, provide only few mechanistic details about the relationship 
between higher order chromatin structure and genome function. Recent advances in 
genomic technologies have led to rapid advances in the study of 
three-dimensional genome organization. In particular, Hi-C has been introduced 
as a method for identifying higher order chromatin interactions genome wide. 
Here we investigate the three-dimensional organization of the human and mouse 
genomes in embryonic stem cells and terminally differentiated cell types at 
unprecedented resolution. We identify large, megabase-sized local chromatin 
interaction domains, which we term 'topological domains', as a pervasive 
structural feature of the genome organization. These domains correlate with 
regions of the genome that constrain the spread of heterochromatin. The domains 
are stable across different cell types and highly conserved across species, 
indicating that topological domains are an inherent property of mammalian 
genomes. Finally, we find that the boundaries of topological domains are 
enriched for the insulator binding protein CTCF, housekeeping genes, transfer 
RNAs and short interspersed element (SINE) retrotransposons, indicating that 
these factors may have a role in establishing the topological domain structure 
of the genome.