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.
Highlights
Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes
The concept of a genome compartmentalized into regulatory neighbourhoods[7,8,9,10,11,12], such as topological-associated domains (TADs)[9,11] and insulated neighbourhoods[7,8,12], was established along with the identification of chromatin loops using Chromosome Conformation Capture (3C) technologies, Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET)[13] and Hi-C14, and the accompanying computational approaches
The Wap gene itself is expressed exclusively in mammary epithelium and its more than 1,000-fold activation during pregnancy is controlled by a tripartite super-enhancer that senses prolactin through the transcription factor STAT5 and likely other mammary-enriched transcription factors[6]
Summary
Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes. 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 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 Ramp[3], despite three separating CTCF sites Their deletion in mice results in elevated expression of Ramp[3] in mammary tissue through augmented promoter–enhancer interactions. It is vital that the transcriptional silence of mammary loci in non-mammary cells does not spread to active neighbouring genes, which could result in their inadvertent silencing with all its potential consequences At this point it is not known whether CTCF sites demarcate highly active mammary super-enhancers from neighbouring genes. Both RAMP3 (ref. 40) and TBRG441 are regulatory proteins and well-defined levels likely ensure biological functions of expressing cells
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