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Nat Commun. 2017 Jul 17;8:16069. doi: 10.1038/ncomms16069.

Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells.

Author information

1
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA.
2
Division of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
3
Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
4
Department of Cell and Developmental Biology &Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea.

Abstract

Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes. Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements. Here, we address these questions in the Wap locus with its mammary-specific super-enhancer separated by CTCF sites from widely expressed genes. Mutational analysis demonstrates that the Wap super-enhancer controls Ramp3, despite three separating CTCF sites. Their deletion in mice results in elevated expression of Ramp3 in mammary tissue through augmented promoter-enhancer interactions. Deletion of the distal CTCF-binding site results in loss of Ramp3 expression in non-mammary tissues. This suggests that CTCF sites are porous borders, allowing a super-enhancer to activate a secondary target. Likewise, CTCF sites shield a widely expressed gene from suppressive influences of a silent locus.

PMID:
28714474
PMCID:
PMC5520053
DOI:
10.1038/ncomms16069
[Indexed for MEDLINE]
Free PMC Article

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