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 territories1. 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 wide2. 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.
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Gene Expression Omnibus
All Hi-C data described in this study have been deposited in the GEO under accession number GSE35156. We have developed a web-based Java tool to visualize the high-resolution Hi-C data at a genomic region of interest that is available at http://chromosome.sdsc.edu/mouse/hi-c/.
We are grateful for the comments from and discussions with Z. Qin, A. Desai and members of the Ren laboratory during the course of the study. We also thank W. Bickmore and R. Eskeland for sharing the FISH data generated in mouse ES cells. This work was supported by funding from the Ludwig Institute for Cancer Research, California Institute for Regenerative Medicine (CIRM, RN2-00905-1) (to B.R.) and NIH (B.R. R01GH003991). J.R.D. is funded by a pre-doctoral training grant from CIRM. Y.S. is supported by a postdoctoral fellowship from the Rett Syndrome Research Foundation.
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