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Cited by 282Genomics and Chromatin DynamicsEstrogen and related hormone effectsChromatin Remodeling and Cancer

Hierarchy within the mammary STAT5-driven Wap super-enhancer

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Shin, Ha Youn, Willi, Michaela, Yoo, Kyung Hyun, Zeng, Xianke, Wang, Chaochen, Metser, Gil, Hennighausen, Lothar·2016·Nature Genetics
DOI 10.1038/ng.3606PMC PMC4963296
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Abstract

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.

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  • Some deviations from enhancer additivity could potentially be explained by steric constraints arising from enhancer competition or involvement of pioneer enhancers, but these considerations may not readily explain other reported cases.

    “Some deviations from enhancer additivity could potentially be explained by steric constraints arising from enhancer competition [519] or involvement of “pioneer enhancers” [525], but these considerations may not readily explain other reported cases [523, 526].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [525]

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Cited by

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Authors
Shin, H. Y., Willi, M., Yoo, K. H., Zeng, X., Wang, C., Metser, G., & Hennighausen, L.
Affiliations
National Institutes of Health (US)
Corresponding author
Hennighausen, Lothar
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2016-07-04
Volume
48
Issue
8
Pages
904-911
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3606
PMC
PMC4963296
OpenAlex
W2469912802
Cited by
282
References
11
Citations by year
2026: 10 · 2025: 23 · 2024: 26 · 2023: 36 · 2022: 31 · 2021: 40 · 2020: 28 · 2019: 15 · 2018: 31 · 2017: 30 · 2016: 12
FWCI
15.25
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Medizinische Universität Innsbruck
  • National Institutes of Health (Z99 DK999999)
  • National Heart, Lung, and Blood Institute
  • National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
super-enhancers, STAT5, mammary gland, NFIB, ELF5, glucocorticoid receptor, MED1, H3K27ac
MeSH terms
Animals, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Mammary Glands, Animal, Milk Proteins, Mutation, Pregnancy, Protein Binding, Transcription, Genetic, Mice, Knockout, STAT5 Transcription Factor, Mice

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