The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements

  1. Peter Fraser1
  1. 1Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
  2. 2University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
  3. 3Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
  4. 4EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom;
  5. 5Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
  6. 6Bioinformatics Group, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
  7. 7Agilent Technologies, Inc., Santa Clara, California 95051, USA;
  8. 8Okinawa Institute for Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan
  1. Corresponding authors: peter.fraser{at}babraham.ac.uk, nicholas.luscombe{at}ucl.ac.uk
  1. 9 These authors contributed equally to this work.

Abstract

The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their long-range interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.

Footnotes

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.185272.114.

  • Freely available online through the Genome Research Open Access option.

  • Received October 3, 2014.
  • Accepted February 11, 2015.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.

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