RT Journal
A1 Ing-Simmons, Elizabeth
A1 Seitan, Vlad C.
A1 Faure, Andre J.
A1 Flicek, Paul
A1 Carroll, Thomas
A1 Dekker, Job
A1 Fisher, Amanda G.
A1 Lenhard, Boris
A1 Merkenschlager, Matthias
T1 Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin
JF Genome Research 
JO Genome Research 
YR 2015 
FD April 01 
VO 25 
IS 4 
SP 504 
OP 513 
DO 10.1101/gr.184986.114 
UL http://genome.cshlp.org/content/25/4/504.abstract 
AB 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.”