Life of mammary-specific super enhancers: how to induce gene activity 10,000-fold during pregnancy

Authors

• HY Shin
• KH Yoo
• S Oh
• G Metser
• LH Hennighausen

Abstract

Differentiation of mammary epithelium during pregnancy is defined by the sequential activation of mammary-specific genes in response to hormonal stimuli. Key to the unprecedented and more than 10,000-fold induction of specific gene sets is the transcription factor (TF) STAT5A. However it is not clear how this common TF can activate mammary-specific genes at this magnitude. In a quest to identify mammary-specific super enhancers we used ChIP-seq to monitor histone modifications and TFs that bind to the more than 300 mammary-specific loci. Common to them was the presence of strong enhancer marks (H3K27ac) that coincided with the binding of several TFs, including STAT5, MED1, GR and NFIB and PolII. Since STAT5 is the immediate responder to hormones controlling mammary epithelium, we used CRISPR/Cas9 gene editing in mice to address its importance in the establishment and function of enhancers. STAT5 binding to three putative enhancers in the most highly activated mammary-specific gene, Wap, was targeted. This led to the discovery of an enhancer hierarchy, both in terms of establishment during pregnancy and functional significance. Notably, establishment and function of the most relevant enhancer was uniquely dependent on the presence of STAT5 binding. In contrast, structure and function of the two other enhancers was only perturbed but not abandoned by the absence of STAT5 binding. We propose that STAT5 binding to specific genomic sequences is the pioneering event in the establishment of hormone-regulated mammary-specific super enhancers. These enhancer complexes are defined by multifaceted TFs that successively assemble during pregnancy and confer lineage specificity.

Scientific Focus Area: Genetics and Genomics

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