Letter | Published:

Capturing pairwise and multi-way chromosomal conformations using chromosomal walks

Nature volume 540, pages 296300 (08 December 2016) | Download Citation

Abstract

Chromosomes are folded into highly compacted structures to accommodate physical constraints within nuclei and to regulate access to genomic information1,2. Recently, global mapping of pairwise contacts showed that loops anchoring topological domains (TADs) are highly conserved between cell types and species3,4,5,6,7,8. Whether pairwise loops9,10,11,12,13,14 synergize to form higher-order structures is still unclear. Here we develop a conformation capture assay to study higher-order organization using chromosomal walks (C-walks) that link multiple genomic loci together into proximity chains in human and mouse cells. This approach captures chromosomal structure at varying scales. Inter-chromosomal contacts constitute only 7–10% of the pairs and are restricted by interfacing TADs. About half of the C-walks stay within one chromosome, and almost half of those are restricted to intra-TAD spaces. C-walks that couple 2–4 TADs indicate stochastic associations between transcriptionally active, early replicating loci. Targeted analysis of thousands of 3-walks anchored at highly expressed genes support pairwise, rather than hub-like, chromosomal topology at active loci. Polycomb-repressed Hox domains are shown by the same approach to enrich for synergistic hubs. Together, the data indicate that chromosomal territories, TADs, and intra-TAD loops are primarily driven by nested, possibly dynamic, pairwise contacts.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Data have been deposited in the Gene Expression Omnibus under accession number GSE77553.

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Acknowledgements

We acknowledge E. Yaffe for help with early stages of the experiments, N. Mor for help with mES cells, and members of the A.T. group for discussions. Research at the A.T. group was supported by the European Research Council (EVOEPIC), Flight Attendant Medical Research Institute (FAMRI), and the Israel Science Foundation (ISF). A.T. is a Kimmel investigator.

Author information

Affiliations

  1. Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel

    • Pedro Olivares-Chauvet
    • , Zohar Mukamel
    • , Aviezer Lifshitz
    • , Omer Schwartzman
    • , Noa Oded Elkayam
    • , Yaniv Lubling
    •  & Amos Tanay
  2. Icahn Institute and Dept. of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA

    • Gintaras Deikus
    •  & Robert P. Sebra

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Contributions

P.O.-C. and A.T. designed the study with help from Z.M. P.O.-C. and Z.M. developed and optimized the experimental approach with help from N.O.E., O.S. and Y.L. P.O.-C. and A.T. developed the algorithmic approaches and analysed the data, with help from A.L., Y.L. and O.S. G.D. and R.B.P. performed PacBio sequencing. P.O.-C. and A.T. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amos Tanay.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This file contains the C-Walk statistics.

  2. 2.

    Supplementary Table 2

    This file contains the 3way-4C bait data base.

  3. 3.

    Supplementary Table 3

    This file contains a list of epigenomic data sets used.

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Publication history

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DOI

https://doi.org/10.1038/nature20158

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