Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin
File(s)gr.184986.114.full.pdf (9.38 MB)
Accepted version
Author(s)
Type
Journal Article
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.”
Date Issued
2015-02-12
Online Publication Date
2015-02-12
2015-03-05T12:44:00Z
Date Acceptance
2015-02-11
ISSN
1054-9803
Publisher
Cold Spring Harbor Laboratory Press
Start Page
504
End Page
513
Journal / Book Title
Genome Research
Volume
25
Issue
4
Copyright Statement
© 2015 by Cold Spring Harbor Laboratory Press
Source Database
pubmed
Sponsor
Wellcome Trust
Identifier
https://genome.cshlp.org/content/25/4/504
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000352139200005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
099276/Z/12/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Genetics & Heredity
EMBRYONIC STEM-CELLS
CHROMATIN ARCHITECTURE
GENOME ORGANIZATION
SUPER-ENHANCERS
IDENTITY GENES
EXPRESSION
CTCF
DIFFERENTIATION
LANDSCAPE
INSULATORS
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Genetics & Heredity
EMBRYONIC STEM-CELLS
CHROMATIN ARCHITECTURE
GENOME ORGANIZATION
SUPER-ENHANCERS
IDENTITY GENES
EXPRESSION
CTCF
DIFFERENTIATION
LANDSCAPE
INSULATORS
Animals
Binding Sites
CCCTC-Binding Factor
Cell Cycle Proteins
Cells, Cultured
Chromosomal Proteins, Non-Histone
Enhancer Elements, Genetic
Gene Expression Regulation
Histones
Mice
Multigene Family
Promoter Regions, Genetic
Protein Binding
Repressor Proteins
Thymocytes
Cells, Cultured
Animals
Mice
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Histones
Repressor Proteins
Gene Expression Regulation
Binding Sites
Protein Binding
Multigene Family
Enhancer Elements, Genetic
Promoter Regions, Genetic
Thymocytes
CCCTC-Binding Factor
Bioinformatics
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2015-02-12