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Iterative correction of Hi-C data reveals hallmarks of chromosome organization - Nature Methods

  • ️Mirny, Leonid A
  • ️Sun Sep 02 2012
  • Article
  • Published: 02 September 2012

Nature Methods volume 9pages 999–1003 (2012)Cite this article

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Abstract

Extracting biologically meaningful information from chromosomal interactions obtained with genome-wide chromosome conformation capture (3C) analyses requires the elimination of systematic biases. We present a computational pipeline that integrates a strategy to map sequencing reads with a data-driven method for iterative correction of biases, yielding genome-wide maps of relative contact probabilities. We validate this ICE (iterative correction and eigenvector decomposition) technique on published data obtained by the high-throughput 3C method Hi-C, and we demonstrate that eigenvector decomposition of the obtained maps provides insights into local chromatin states, global patterns of chromosomal interactions, and the conserved organization of human and mouse chromosomes.

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References

  1. Cheung, M.S., Down, T.A., Latorre, I. & Ahringer, J. Systematic bias in high-throughput sequencing data and its correction by BEADS. Nucleic Acids Res. 39, e103 (2011).

    Article  CAS  Google Scholar 

  2. Quail, M.A. et al. A large genome center's improvements to the Illumina sequencing system. Nat. Methods 5, 1005–1010 (2008).

    Article  CAS  Google Scholar 

  3. Teytelman, L. et al. Impact of chromatin structures on DNA processing for genomic analyses. PLoS ONE 4, e6700 (2009).

    Article  Google Scholar 

  4. 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 

  5. Zhao, Z. et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat. Genet. 38, 1341–1347 (2006).

    Article  CAS  Google Scholar 

  6. Dostie, J. et al. Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res. 16, 1299–1309 (2006).

    Article  CAS  Google Scholar 

  7. 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 

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

    Article  CAS  Google Scholar 

  9. Kalhor, R., Tjong, H., Jayathiilaka, N., Alber, N. & Chen, L. Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat. Biotechnol. 30, 90–98 (2012).

    Article  CAS  Google Scholar 

  10. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. van Steensel, B. & Dekker, J. Genomics tools for unraveling chromosome architecture. Nat. Biotechnol. 28, 1089–1095 (2010).

    Article  CAS  Google Scholar 

  13. Dixon, J.R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  Google Scholar 

  14. Nora, E.P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).

    Article  CAS  Google Scholar 

  15. Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. ENCODE Project Consortium et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

  18. Kent, W.J., Baertsch, R., Hinrichs, A., Miller, W. & Haussler, D. Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes. Proc. Natl. Acad. Sci. USA 100, 11484–11489 (2003).

    Article  CAS  Google Scholar 

  19. Weierich, C. et al. Three-dimensional arrangements of centromeres and telomeres in nuclei of human and murine lymphocytes. Chromosome Res. 11, 485–502 (2003).

    Article  CAS  Google Scholar 

  20. Alcobia, I., Quina, A.S., Neves, H., Clode, N. & Parreira, L. The spatial organization of centromeric heterochromatin during normal human lymphopoiesis: evidence for ontogenically determined spatial patterns. Exp. Cell Res. 290, 358–369 (2003).

    Article  CAS  Google Scholar 

  21. Ding, C. & He, X. K-means clustering via principal component analysis. Proc. Intl. Conf. Machine Learning (ICML 2004) 225–232 (2004).

  22. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  Google Scholar 

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Acknowledgements

The authors are grateful to K. Korolev for many productive discussions. The work of M.I., G.F., A.G. and L.M. were supported by the US National Cancer Institute Physical Sciences–Oncology Center at MIT (U54CA143874). This work was supported by US National Institutes of Health grants HG003143 (to J.D.) and F32GM100617 (to R.P.M.) and by a W.M. Keck Foundation Distinguished Young Scholar in Medical Research Award (to J.D.).

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Author notes

  1. Maxim Imakaev and Geoffrey Fudenberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA

    Maxim Imakaev, Anton Goloborodko & Leonid A Mirny

  2. Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, USA

    Geoffrey Fudenberg & Leonid A Mirny

  3. Department of Biochemistry and Molecular Pharmacology, Program in Systems Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Rachel Patton McCord, Natalia Naumova, Bryan R Lajoie & Job Dekker

  4. Institute for Medical Engineering and Science, MIT, Cambridge, Massachusetts, USA.,

    Leonid A Mirny

Authors

  1. Maxim Imakaev

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  2. Geoffrey Fudenberg

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  3. Rachel Patton McCord

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  4. Natalia Naumova

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  5. Anton Goloborodko

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  6. Bryan R Lajoie

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  7. Job Dekker

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  8. Leonid A Mirny

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Contributions

M.I. developed the iterative correction procedure. M.I. and G.F. developed data analysis tools. M.I. and A.G. developed and maintain publicly available software. M.I., G.F., R.P.M. and A.G. performed data analysis. M.I., G.F., R.P.M., N.N., A.G., B.R.L., J.D. and L.A.M. contributed to conceiving the study and wrote the paper.

Corresponding authors

Correspondence to Job Dekker or Leonid A Mirny.

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The authors declare no competing financial interests.

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Imakaev, M., Fudenberg, G., McCord, R. et al. Iterative correction of Hi-C data reveals hallmarks of chromosome organization. Nat Methods 9, 999–1003 (2012). https://doi.org/10.1038/nmeth.2148

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  • Received: 14 May 2012

  • Accepted: 04 August 2012

  • Published: 02 September 2012

  • Issue Date: October 2012

  • DOI: https://doi.org/10.1038/nmeth.2148

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