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

Lineage-specific genetic programs rely on cell-restricted super-enhancers but it is not clear whether they selectively engage with their associated promoters to attain maximum activity. Exploiting the highly expressed Wap gene, we investigate the relative contributions of the super-enhancer and promoter in mammary tissue during lactation. Employing ChIP-seq profiling and mouse genetics, we uncover a selective lineage-specific promoter-enhancer synergy. Mechanistically, a chromatin platform permissive for high level expression develops in the native promoter-enhancer configuration but not with a heterologous promoter. While this promoter-enhancer synergy permits the induction of gene expression during pregnancy, post-transcriptional mechanisms need to be invoked to account for the high levels of Wap mRNA during lactation. Taken together, our data reveal that lineage-specific enhancer-promoter synergy and post-transcriptional regulation are critical for mammary gene regulation during pregnancy and lactation. Wap super-enhancer or super-enhancer-promoter was fused to gene Tbrg4 by CRISPR/Cas9-mediated genomic deletion. Therefore mouse lines seTbrg4,ΔE/wTbrg4 and WT/wTbrg4 were generated. ChIP-seq of histone modifications, STAT5, Pol II and RNA-seq were performed in mammary glands at lactation day 10 (L10) from the mice.