Abstract
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.
Highlights
Super-enhancers (SEs) are key components in the control of lineage-specific transcription programs[1]
An analysis of lactating mammary tissue from the SETbrg[4] mice revealed a five-fold increase in Tbrg[4] mRNA (Fig. 1b), demonstrating that lineage-specific Wap-SE has the capacity to activate a heterologous promoter. This activation was significantly lower than the 1000fold upregulation of the endogenous Wap gene with the Wap-SE (Fig. 1b), suggesting the presence of additional key elements that communicate with this SE
This pattern is true for some genes, the annotation and definition of regulatory elements is currently being expanded, as enhancers have been identified in promoters and enhancers can contain promoters[18,19]
Summary
Super-enhancers (SEs) are key components in the control of lineage-specific transcription programs[1]. They feature platforms with a high density of transcription factors (TFs) and other regulatory components, such as RNA polymerase II (Pol II) It remains unclear why tissue-specific genes associated with structurally equivalent SEs are expressed at widely different levels, ranging by several orders of magnitude. RNA-seq experiments have revealed that the expression of genes associated with mammary SEs ranges from less than one Fragments Per Kilobase of transcripts per Million mapped reads (FPKM) to more than 500,000 FPKM, and more than one-half of these expressed genes are not induced during pregnancy[2] We speculated that this enormous diversity of gene expression is inherent to the structure and activity of the enhancers but is caused by the interplay of specific and unique promoter–enhancers. Enhancer–promoter specificity was suggested by self-transcribing active regulatory region sequencing (STARR-seq) of Drosophila[5] and the presence of promoterspecific transcriptional cofactors[6], decisive genetic studies to validate promoter–enhancer synergy in vivo have not been
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