title: Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin.
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."
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom; Computational Regulatory Genomics Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Elizabeth
authors: E
authors: Ing-Simmons
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Vlad C
authors: VC
authors: Seitan
authors: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors: Andre J
authors: AJ
authors: Faure
authors: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors: Paul
authors: P
authors: Flicek
authors: Computing and Bioinformatics Facility, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Thomas
authors: T
authors: Carroll
authors: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Job
authors: J
authors: Dekker
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Amanda G
authors: AG
authors: Fisher
authors: Computational Regulatory Genomics Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Boris
authors: B
authors: Lenhard
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom; matthias.merkenschlager@csc.mrc.ac.uk.
authors: Matthias
authors: M
authors: Merkenschlager
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006657:Histones / Q000235:genetics; D051379:Mice; D005810:Multigene Family / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology*; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D012097:Repressor Proteins; D000097722:Cohesins; C000619698:Ctcf protein, mouse