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Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture

Nature Genetics volume 43, pages 1059–1065 (2011)Cite this article

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Abstract

Hi-C experiments measure the probability of physical proximity between pairs of chromosomal loci on a genomic scale. We report on several systematic biases that substantially affect the Hi-C experimental procedure, including the distance between restriction sites, the GC content of trimmed ligation junctions and sequence uniqueness. To address these biases, we introduce an integrated probabilistic background model and develop algorithms to estimate its parameters and renormalize Hi-C data. Analysis of corrected human lymphoblast contact maps provides genome-wide evidence for interchromosomal aggregation of active chromatin marks, including DNase-hypersensitive sites and transcriptionally active foci. We observe extensive long-range (up to 400 kb) cis interactions at active promoters and derive asymmetric contact profiles next to transcription start sites and CTCF binding sites. Clusters of interacting chromosomal domains suggest physical separation of centromere-proximal and centromere-distal regions. These results provide a computational basis for the inference of chromosomal architectures from Hi-C experiments.

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Figure 1: Sources of Hi-C biases.
Figure 2: Model performance.
Figure 3: Chromosomal architecture around active chromatin.
Figure 4: Chromosomal architecture around CTCF binding sites.
Figure 5: Contact map clustering.

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References

  1. Fullwood, M.J. et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462, 58–64 (2009).

    Article  CAS  Google Scholar 

  2. Bantignies, F. et al. Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. Cell 144, 214–226 (2011).

    Article  CAS  Google Scholar 

  3. Schoenfelder, S. et al. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat. Genet. 42, 53–61 (2010).

    Article  CAS  Google Scholar 

  4. Fraser, P. & Bickmore, W. Nuclear organization of the genome and the potential for gene regulation. Nature 447, 413–417 (2007).

    Article  CAS  Google Scholar 

  5. Miele, A. & Dekker, J. Mapping cis- and trans- chromatin interaction networks using chromosome conformation capture (3C). Methods Mol. Biol. 464, 105–121 (2009).

    Article  Google Scholar 

  6. Hagège, H. et al. Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nat. Protoc. 2, 1722–1733 (2007).

    Article  Google Scholar 

  7. Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    Article  CAS  Google Scholar 

  8. Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat. Genet. 38, 1348–1354 (2006).

    Article  CAS  Google Scholar 

  9. Simonis, M. et al. High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology. Nat. Methods 6, 837–842 (2009).

    Article  CAS  Google Scholar 

  10. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  Google Scholar 

  11. Dekker, J. The three 'C' s of chromosome conformation capture: controls, controls, controls. Nat. Methods 3, 17–21 (2006).

    Article  CAS  Google Scholar 

  12. Dohm, J.C., Lottaz, C., Borodina, T. & Himmelbauer, H. Substantial biases in ultra-short read data sets from high-throughput DNA sequencing. Nucleic Acids Res. 36, e105 (2008).

    Article  Google Scholar 

  13. Aird, D. et al. Analyzing and minimizing PCR amplification bias in Illumina sequencing libraries. Genome Biol. 12, R18 (2011).

    Article  CAS  Google Scholar 

  14. Mitchell, J.A. & Fraser, P. Transcription factories are nuclear subcompartments that remain in the absence of transcription. Genes Dev. 22, 20–25 (2008).

    Article  CAS  Google Scholar 

  15. Sexton, T., Umlauf, D., Kurukuti, S. & Fraser, P. The role of transcription factories in large-scale structure and dynamics of interphase chromatin. Semin. Cell Dev. Biol. 18, 691–697 (2007).

    Article  CAS  Google Scholar 

  16. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).

    Article  CAS  Google Scholar 

  17. Hakim, O. et al. Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements. Genome Res. 21, 697–706 (2011).

    Article  CAS  Google Scholar 

  18. Phillips, J.E. & Corces, V.G. CTCF: master weaver of the genome. Cell 137, 1194–1211 (2009).

    Article  Google Scholar 

  19. Fu, Y., Sinha, M., Peterson, C.L. & Weng, Z. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 4, e1000138 (2008).

    Article  Google Scholar 

  20. Handoko, L. et al. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat. Genet. 43, 630–638 (2011).

    Article  CAS  Google Scholar 

  21. Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    Article  CAS  Google Scholar 

  22. Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome–nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010).

    Article  CAS  Google Scholar 

  23. Duan, Z. et al. A three-dimensional model of the yeast genome. Nature 465, 363–367 (2010).

    Article  CAS  Google Scholar 

  24. Li, H., Ruan, J. & Durbin, R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 18, 1851–1858 (2008).

    Article  CAS  Google Scholar 

  25. Sabo, P.J. et al. Discovery of functional noncoding elements by digital analysis of chromatin structure. Proc. Natl. Acad. Sci. USA 101, 16837–16842 (2004).

    Article  CAS  Google Scholar 

  26. Mikkelsen, T.S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank W. de Laat for discussions and members of the Tanay group for critical reading of the manuscript. Research at A.T.'s laboratory was supported by the Israeli Science Foundation and by the EPIGENESYS FP7 program of the European Commission.

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Authors and Affiliations

  1. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

    Eitan Yaffe & Amos Tanay

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  1. Eitan Yaffe
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  2. Amos Tanay
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Contributions

E.Y. and A.T. conceived and performed the analysis. E.Y and A.T wrote the article.

Corresponding author

Correspondence to Amos Tanay.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8 and Supplementary Table 1 (PDF 2719 kb)

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Yaffe, E., Tanay, A. Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture. Nat Genet 43, 1059–1065 (2011). https://doi.org/10.1038/ng.947

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