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Topological domains in mammalian genomes identified by analysis of chromatin interactions

Nature volume 485, pages 376–380 (2012)Cite this article

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Abstract

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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Figure 1: Topological domains in the mouse ES cell genome.
Figure 2: Topological boundaries demonstrate classical insulator or barrier element features.
Figure 3: Boundaries are shared across cell types and conserved in evolution.
Figure 4: Boundary regions are enriched for housekeeping genes.

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Gene Expression Omnibus

Data deposits

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/.

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Acknowledgements

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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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Jesse R. Dixon, Siddarth Selvaraj, Feng Yue, Audrey Kim, Yan Li, Yin Shen & Bing Ren

  2. Medical Scientist Training Program, University of California, San Diego, La Jolla, California 92093, USA ,

    Jesse R. Dixon

  3. Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093, USA ,

    Jesse R. Dixon

  4. Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California 92093, USA ,

    Siddarth Selvaraj

  5. Department of Statistics, Harvard University, 1 Oxford Street, Cambridge, Massachusetts 02138, USA,

    Ming Hu & Jun S. Liu

  6. Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, Institute of Genomic Medicine, UCSD Moores Cancer Center, 9500 Gilman Drive, La Jolla, California 92093, USA,

    Bing Ren

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  1. Jesse R. Dixon
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Contributions

J.R.D. and B.R. designed the studies. J.R.D., A.K., Y.L. and Y.S. conducted the Hi-C experiments; J.R.D., S.S. and F.Y. carried out the data analysis; J.S.L. and M.H. provided insight for analysis; F.Y. built the supporting website; J.R.D. and B.R. prepared the manuscript.

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Correspondence to Bing Ren.

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The authors declare no competing financial interests.

Supplementary information

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Dixon, J., Selvaraj, S., Yue, F. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012). https://doi.org/10.1038/nature11082

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