Genome architectures revealed by tethered chromosome conformation capture and population-based modeling

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Abstract

We describe tethered conformation capture (TCC), a method for genome-wide mapping of chromatin interactions. By performing ligations on solid substrates rather than in solution, TCC substantially enhances the signal-to-noise ratio, thereby facilitating a detailed analysis of interactions within and between chromosomes. We identified a group of regions in each chromosome in human cells that account for the majority of interchromosomal interactions. These regions are marked by high transcriptional activity, suggesting that their interactions are mediated by transcriptional machinery. Each of these regions interacts with numerous other such regions throughout the genome in an indiscriminate fashion, partly driven by the accessibility of the partners. As a different combination of interactions is likely present in different cells, we developed a computational method to translate the TCC data into physical chromatin contacts in a population of three-dimensional genome structures. Statistical analysis of the resulting population demonstrates that the indiscriminate properties of interchromosomal interactions are consistent with the well-known architectural features of the human genome.

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Figure 1: Overview of TCC.
Figure 2: Tethering improves the signal-to-noise ratio of conformation capture.
Figure 3: Intrachromosomal interactions.
Figure 4: Interchromosomal interactions.
Figure 5: Coarse-graining of the contact frequency maps and structural representation of the genome.
Figure 6: Population-based analysis of chromosome territory localizations in the nucleus.

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Acknowledgements

The authors would like to acknowledge P. Laird, J. Knowles and J. Aman and the USC Epigenome Center for assistance in high-throughput sequencing, M. Michael and A. Williams for assistance in confocal microscopy, N. Bottini and Q.-L. Ying and members of their laboratories for assistance in cell culture, A.D. Smith for access to cluster computing, I. Slaymaker for graphic design and the integrative modeling platform team for support. Structure calculations were done on USC HPCC. We also thank N. Arnheim, A.D. Smith, O. Aparicio, S. Forsburg, W. Li, M.S. Madhusudhan, K. Gong, S. Srivastava, S. Al-Bassam, M. Murphy, J. Peace and Z. Ostrow for useful discussions and comments on the manuscript. This work is supported by Human Frontier Science Program grant RGY0079/2009-C to F.A., Alfred P. Sloan Foundation grant to F.A.; US National Institutes of Health (NIH) grants GM064642 and GM077320 to L.C., NIH grant GM096089 to F.A. and NIH grant RR022220 to F.A. and L.C. F.A. is a Pew Scholar in Biomedical Sciences, supported by the Pew Charitable Trusts.

Author information

R.K. and L.C. conceived the TCC technique and R.K. performed the experiments and analyzed the contact data. R.K. and N.J. performed the FISH experiments and analyzed the results. H.T. and F.A. conceived the modeling strategy, and R.K. and L.C. provided input and discussions. H.T. performed the modeling experiments and analysis. R.K., F.A., H.T. and L.C. wrote the manuscript. All authors commented on and revised the manuscript. F.A. and L.C. supervised the project.

Correspondence to Frank Alber or Lin Chen.

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A provisional patent for TCC is under review.

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Kalhor, R., Tjong, H., Jayathilaka, N. et al. Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat Biotechnol 30, 90–98 (2012) doi:10.1038/nbt.2057

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