Cohesin stabilization at promoters and enhancers by common transcription factors and chromatin regulators

Cohesin is a major regulator of three-dimensional genome organization and gene expression. Cohesin associates with DNA and dynamically extrudes a DNA loop, often bringing two cis-regulatory elements physically close together. Extruding cohesin molecules can be stalled or stabilized when they encounter a CTCF insulator protein on DNA, thereby anchoring a DNA loop. However, many enhancer-promoter loops that are bound by cohesin lack CTCF and it is not clear how cohesin is stabilized at or recruited to these sites in the genome.

Here, we investigated the localization of cohesin with common chromatin regulators and transcription factors on the mouse embryonic stem cell genome. The SP1 and NFYA transcription factors are ubiquitously expressed proteins known to regulate expression of genes associated with a variety of cellular processes, while WDR5 is a ubiquitous core component of multiple chromatin regulatory complexes. We found that cohesin co-bound promoters and enhancers with WDR5, with SP1, or with NFYA in mESCs. Cohesin physically interacted with and colocalized with WDR5, with SP1, or with NFYA on the same molecule of chromatin. Strikingly, depletion of WDR5, SP1, or NFYA caused a decrease in cohesin binding at shared binding sites, while depletion of cohesin did not alter binding of WDR5, SP1, or NFYA on the genome.

These results indicate that common transcription factors and chromatin regulators stabilize cohesin at specific sites in chromatin and may thereby serve as structural regulators of enhancer-promoter loops via the stabilization of cohesin.