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ArtikelHierarchy within the Mammary STAT5-Driven Wap Super-Enhancer  
Oleh: Ha Youn Shin ; Willi, Michaela ; Kyung Hyun Yoo ; Xianke Zeng ; Chaochen Wang ; Metser, Gil ; Hennighausen, Lothar
Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Nature Genetics vol. 48 no. 08 (Aug. 2016), page 904-911.
Topik: Epigenomics; Gene Regulation; Mutagenesis
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Isi artikelSuper-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.
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