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."

journal_name

Genome Res

journal_title

Genome research

authors

Ing-Simmons E,Seitan VC,Faure AJ,Flicek P,Carroll T,Dekker J,Fisher AG,Lenhard B,Merkenschlager M

doi

10.1101/gr.184986.114

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

504-13

issue

4

eissn

1088-9051

issn

1549-5469

pii

gr.184986.114

journal_volume

25

pub_type

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