Article | Published:

Single-cell Hi-C reveals cell-to-cell variability in chromosome structure

Nature volume 502, pages 5964 (03 October 2013) | Download Citation

Abstract

Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair. Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei. Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales. Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation. Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns.

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Gene Expression Omnibus

Data deposits

Data deposited in NCBIs Gene Expression Omnibus and are accessible through GEO Series accession number GSE48262.

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Acknowledgements

The authors thank I. Clay, S. Wingett, K. Tabbada, D. Bolland, S. Walker, S. Andrews, M. Spivakov, N. Cope, L. Harewood and W. Boucher for assistance. This work was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council (to P.F.), the MODHEP project, the Israel Science Foundation (to A.T.) and the Wellcome Trust (to E.D.L.).

Author information

Author notes

    • Takashi Nagano
    • , Yaniv Lubling
    •  & Tim J. Stevens

    These authors contributed equally to this work.

Affiliations

  1. Nuclear Dynamics Programme, The Babraham Institute, Cambridge CB22 3AT, UK

    • Takashi Nagano
    • , Stefan Schoenfelder
    •  & Peter Fraser
  2. Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel

    • Yaniv Lubling
    • , Eitan Yaffe
    •  & Amos Tanay
  3. Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK

    • Tim J. Stevens
    •  & Ernest D. Laue
  4. Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK

    • Wendy Dean

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Contributions

T.N. and P.F. devised the single-cell Hi-C method. T.N. performed single-cell Hi-C and DNA FISH experiments. S.S. carried out ensemble Hi-C experiments. W.D. microscopically isolated single cells. Y.L., E.Y. and A.T. processed and statistically analysed the sequence data. T.J.S. and E.D.L. developed the approach to structural modelling and analysed X-chromosome structures. T.J.S. wrote the software for three-dimensional modelling, analysis and visualisation of chromosome structures. T.N., Y.L., T.J.S., E.D.L., A.T. and P.F. contributed to writing the manuscript, with inputs from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ernest D. Laue or Amos Tanay or Peter Fraser.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Text and Data and Supplementary References.

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    Supplementary Data

    This file contains Supplementary table 1.

Videos

  1. 1.

    Bundle of five low-resolution X chromosome models with epigenomic features coloured as indicated for cell-1

    Bundle of five low-resolution X chromosome models with epigenomic features coloured as indicated for cell-1.

  2. 2.

    Bundle of five low-resolution X chromosome models with epigenomic features coloured as indicated for cell-2

    Bundle of five low-resolution X chromosome models with epigenomic features coloured as indicated for cell-2.

  3. 3.

    Surface rendered fine-scale X chromosome models with genomic and epigenomic features coloured as indicated for cell-1

    Surface rendered fine-scale X chromosome models with genomic and epigenomic features coloured as indicated for cell-1.

  4. 4.

    Surface rendered fine-scale X chromosome models with genomic and epigenomic features coloured as indicated for cell-2

    Surface rendered fine-scale X chromosome models with genomic and epigenomic features coloured as indicated for cell-2.

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DOI

https://doi.org/10.1038/nature12593

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