Fig. 9: Model for the regulation of the shared casein mammary-salivary locus by a dual specific super-enhancer, gene-specific local enhancers and promoters.
a Heatmap shows relative gene expression levels of genes in the Casein locus in the various mutant mice compared to WT mice at day 18 of pregnancy (p18) or day one of lactation (L1). DE distal enhancer. The data from the Csn2, Csn3 and ΔSE mice are from this study, and the Csn1s2b mutant has been reported earlier25. b The super-enhancer preferentially activates the Csn1s2b, Csn3 and Odam genes and marginally the Csn1s1, Csn2 and Csn1s2a genes in mammary gland during pregnancy and regulates the promoters of Odam, Fdcsp and Csn3 genes in salivary gland tissue. c The Csn2 gene is characterized by distinct enhancer and promoter elements, both harboring STAT5 binding sites (GAS motifs) that are bound by STAT5 during lactation. Individually, neither the enhancers nor the promoter STAT5 sites are absolutely required for efficient gene activation, suggesting that they can partially compensate for each other’s activity. Combined inactivation of the distal enhancers and the promoter STAT5 site completely abrogates Csn2 expression suggesting synergism during pregnancy and lactation. Also, neighboring mammary genes are not impacted by the Csn2 enhancer and promoter elements. This distinguishes them from Epromoters51,52 that bind STAT TFs and have been identified in interferon-response genes. In addition to their own native gene, Epromoters also control the expression of neighboring genes. Neither Epromoter-associated genes nor neighboring genes harbor classical distal enhancers. The graphs were created with BioRender.com. Source data are provided as a Source Data file.
