Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin
- Elizabeth Ing-Simmons1,
- Vlad Seitan1,
- Andre Faure2,
- Paul Flicek2,
- Thomas Carroll1,
- Job Dekker3,
- Amanda Fisher1,
- Boris Lenhard1 and
- Matthias Merkenschlager1,4
- 1 Imperial College London;
- 2 European Bioinformatics Institute;
- 3 University of Massachusetts Medical School, Worcester
- ↵* Corresponding author; email: matthias.merkenschlager{at}csc.mrc.ac.uk
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 remained 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 3-D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from non-cycling 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 where spatial clustering of enhancer elements acts as a unified mechanism for both, enhancer-promoter 'connections' and 'insulation'.
- Received September 27, 2014.
- Accepted February 11, 2015.
- Published by Cold Spring Harbor Laboratory Press
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