Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin
- Elizabeth Ing-Simmons1,2,7,
- Vlad C. Seitan1,7,
- Andre J. Faure3,8,
- Paul Flicek3,4,
- Thomas Carroll5,
- Job Dekker6,
- Amanda G. Fisher1,
- Boris Lenhard2 and
- Matthias Merkenschlager1
- 1Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
- 2Computational Regulatory Genomics Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
- 3European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom;
- 4Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
- 5Computing and Bioinformatics Facility, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
- 6Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
- Corresponding author: matthias.merkenschlager{at}csc.mrc.ac.uk
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↵7 These authors contributed equally to this work.
Abstract
In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or “super-enhancers” in mouse thymocytes. Using local and global chromosome conformation capture, we demonstrate that enhancer elements associate not just in linear sequence, but also in 3D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from noncycling thymocytes preserved enhancer position, H3K27ac, H4K4me1, and enhancer transcription, but weakened interactions between enhancers. Interestingly, ∼50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation in which spatial clustering of enhancer elements acts as a unified mechanism for both enhancer-promoter “connections” and “insulation.”
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.184986.114.
- Received September 27, 2014.
- Accepted February 11, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
