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Genome Res. 2015 Apr;25(4):582-97. doi: 10.1101/gr.185272.114. Epub 2015 Mar 9.

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

Author information

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

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.

PMID:
25752748
PMCID:
PMC4381529
DOI:
10.1101/gr.185272.114
[Indexed for MEDLINE]
Free PMC Article

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