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Interdependence of a mammary-specific super-enhancer and its native promoter facilitates gene activation during pregnancy

ABSTRACT: Lineage-specific genetic programs rely on cell-restricted super-enhancers, platforms for high-density occupation by transcription factors. It is not known whether super-enhancers synergize specifically with their native promoters or provide autonomous regulatory platforms. Here we investigate the ability of the mammary Wap super-enhancer to activate the promoter of the juxtaposed and ubiquitously expressed Tbrg4 gene in the mouse mammary gland. The Wap super-enhancer was fused, by itself or in combination with its promoter, with the Tbrg4 gene. While the Wap super-enhancer activated the Tbrg4 promoter five-fold, the combination of Wap super-enhancer and promoter resulted in an 80-fold gene activation, demonstrating lineage-specific promoter-enhancer synergy. Employing ChIP-seq profiling, we uncover a chromatin platform permissive for high level expression that develops in the native promoter-enhancer context but not with a heterologous promoter. Post-transcriptional mechanisms through the Wap 3’UTR have been proposed to account for the exceptional high mRNA levels during lactation, but our mouse genetic experiments failed to support this. Lastly, we discovered that the CREB transcription factor is an integral part of the Tbrg4 promoter but not essential for its function. Taken together, our data reveal that lineage-specific enhancer-promoter synergy is critical for mammary gene regulation during pregnancy and lactation.

ORGANISM(S): Mus musculus

PROVIDER: GSE145193 | GEO | 2020/03/24

REPOSITORIES: GEO

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Lineage-specific super-enhancer activates genes in a promoter-selective manner

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