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| Status |
Public on May 31, 2016 |
| Title |
Hierarchy within the mammary STAT5-driven Wap super-enhancer |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, 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 three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes.
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| Overall design |
ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, RNA Pol II, and H3K4me3 in wild type (WT) mammary tissues at day one of lactation (L1), and ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, and H3K4me3 in WT mammary tissues at day 13 of pregnancy (p13). ChIP-Seq for STAT5A, GR, H3K27ac in Wap-delE1a, -delE1b, -delE1c, -delE2, -delE3, -delE1a_delE2, -delE2_delE3 and -delE1a_delE2_delE3 mutant mammary tissues at L1, and ChIP-Seq for NFIB and ELF5 in Wap-delE1b and -delE1c mutant mammary tissues at L1. ChIP-Seq for H3K4me3 in mammary-epthelial cells at p13 and L1. DNase-seq in WT mammary tissues at L1 and DNase-seq in Wap-delE1a, -delE1c, and -delE3 mutant mammary tissues at L1. ChIP-seq for STAT5A, H3K27ac in WT mammary tissues at p14, ChIP-seq for STAT5A, H3K27ac in WT mammary tissues at p16, and ChIP-seq for CTCF in in WT mammary tissues at L1.
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| Contributor(s) |
Shin H, Willi M, Yoo K, Zeng X, Wang C, Metser G, Hennighausen L |
| Citation(s) |
27376239, 36232979 |
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| Submission date |
Nov 09, 2015 |
| Last update date |
Oct 31, 2022 |
| Contact name |
Michaela Willi |
| Organization name |
NIH
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| Department |
NIDDK
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| Street address |
9000 Rockville Pike
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| City |
Bethesda |
| ZIP/Postal code |
20814 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (82)
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| Relations |
| BioProject |
PRJNA301617 |
| SRA |
SRP065971 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE74826_RAW.tar |
6.2 Gb |
(http)(custom) |
TAR (of BEDGRAPH) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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