The interdependence of mammary-specific super-enhancers and their native promoters facilitates gene activation during pregnancy.

Lineage-specific genetic programs rely on cell-restricted super-enhancers, which are platforms for high-density transcription factor occupation. It is not known whether super-enhancers synergize specifically with their native promoters or provide autonomous and independent regulatory platforms. Here, we investigated 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, alone or in combination with the Wap promoter, to the Tbrg4 gene. While the super-enhancer increased the expression of the Tbrg4 promoter five-fold, the combination of the super-enhancer and promoter resulted in 80-fold gene upregulation, demonstrating lineage-specific promoter–enhancer synergy. Employing ChIP-seq profiling to determine transcription factor binding and identify activating histone marks, we uncovered a chromatin platform that enables the high-level expression of the native promoter–enhancer but not the heterologous promoter. Taken together, our data reveal that lineage-specific enhancer–promoter synergy is critical for mammary gene regulation during pregnancy and lactation. Super-enhancers are regions of DNA that highly activate the expression of specific genes. Research led by H.K.L. and L.H. at the National Institutes of Health, USA, now demonstrate that a super-enhancer is much more effective when operating in synergy with its associated promoter, another gene-controlling element. They investigated super-enhancer and promoter synergy in mouse mammary gland cells. A mammary super-enhancer achieved a 5-fold activation of a gene with a common promoter, in contrast to an 80-fold activation with its own promoter together. The findings reveal that this synergy is critical for gene regulation in the mammary gland during pregnancy and lactation. They also help resolve the general issue of whether super-enhancers act independently or, as found here, can work together with a specific promoters in cell-specific genetic programs.