Abstract

Transcriptional control in large genomes often requires looping interactions between distal DNA elements, such as enhancers and target promoters. Current chromosome conformation capture techniques do not offer sufficiently high resolution to interrogate these regulatory interactions on a genomic scale. Here we use Capture Hi-C (CHi-C), an adapted genome conformation assay, to examine the long-range interactions of almost 22,000 promoters in 2 human blood cell types. We identify over 1.6 million shared and cell type–restricted interactions spanning hundreds of kilobases between promoters and distal loci. Transcriptionally active genes contact enhancer-like elements, whereas transcriptionally inactive genes interact with previously uncharacterized elements marked by repressive features that may act as long-range silencers. Finally, we show that interacting loci are enriched for disease-associated SNPs, suggesting how distal mutations may disrupt the regulation of relevant genes. This study provides new insights and accessible tools to dissect the regulatory interactions that underlie normal and aberrant gene regulation.

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Acknowledgements

We thank E. Darbo for assistance in data analysis and K. Tabbada for sequencing. This work was supported by a Leukaemia and Lymphoma Research Fellowship (C.S.O.), the Framework Programme 7 Epigenesys Network of Excellence (B.M., N.M.L.), Cancer Research UK (B.M., F.T.-C., N.M.L.), UCL (B.M., N.M.L.), OIST (F.T.-C., N.M.L.) and the Wellcome Trust (N.M.L.).

Author information

Author notes

    • Filipe Tavares-Cadete

    Present address: Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.

    • Emily LeProust

    Present address: Twist Bioscience, San Francisco, California, USA.

    • Borbala Mifsud
    • , Filipe Tavares-Cadete
    •  & Alice N Young

    These authors contributed equally to this work.

Affiliations

  1. The Francis Crick Institute, London, UK.

    • Borbala Mifsud
    • , Filipe Tavares-Cadete
    • , Robert Sugar
    •  & Nicholas M Luscombe
  2. UCL Genetics Institute, University College London, London, UK.

    • Borbala Mifsud
    •  & Nicholas M Luscombe
  3. Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK.

    • Alice N Young
    • , Stefan Schoenfelder
    • , Lauren Ferreira
    • , Philip A Ewels
    • , Peter Fraser
    •  & Cameron S Osborne
  4. Bioinformatics Group, Babraham Institute, Cambridge, UK.

    • Steven W Wingett
    •  & Simon Andrews
  5. Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.

    • William Grey
    •  & Cameron S Osborne
  6. Diagnostics and Genomics Division, Agilent Technologies, Santa Clara, California, USA.

    • Bram Herman
    • , Scott Happe
    • , Andy Higgs
    •  & Emily LeProust
  7. Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.

    • George A Follows
  8. Okinawa Institute of Science and Technology, Okinawa, Japan.

    • Nicholas M Luscombe

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Contributions

C.S.O. conceived the study. A.N.Y., S.S., S.A., P.F. and C.S.O. designed the experiments. A.N.Y., S.S., L.F., W.G. and C.S.O. performed the experiments. A.N.Y., L.F., W.G. and C.S.O. analyzed the data. B.M., F.T.-C., R.S., S.W.W., S.A., P.A.E. and N.M.L. carried out the bioinformatics analyses. B.M., F.T.-C., R.S., S.W.W. and N.M.L. carried out the statistical analyses. B.H., S.H., A.H., E.L. and G.A.F. provided reagents. B.M., F.T.-C., N.M.L. and C.S.O. wrote the manuscript with contributions from all authors.

Competing interests

The Babraham Institute has filed a patent application relating to the content of this manuscript (PCT/GB2014/052664).

Corresponding authors

Correspondence to Nicholas M Luscombe or Cameron S Osborne.

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DOI

https://doi.org/10.1038/ng.3286

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