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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.

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


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.

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