Hierarchy within the mammary STAT5-driven Wap super-enhancer

Nat Genet. 2016 Aug;48(8):904-911. doi: 10.1038/ng.3606. Epub 2016 Jul 4.


Super-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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Enhancer Elements, Genetic / genetics*
  • Female
  • Gene Expression Regulation*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Knockout
  • Milk Proteins / genetics*
  • Milk Proteins / metabolism
  • Mutation / genetics
  • Pregnancy
  • Protein Binding
  • STAT5 Transcription Factor / metabolism*
  • Transcription, Genetic / genetics*


  • Milk Proteins
  • STAT5 Transcription Factor
  • whey acidic proteins