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Hierarchy 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
Ketersediaan
Perpustakaan FK
Nomor Panggil:
N12.K
Non-tandon:
1 (dapat dipinjam: 0)
Tandon:
tidak ada
Lihat Detail Induk
Isi artikel
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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