Hierarchy within the mammary STAT5-driven Wap super-enhancer
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.
Errataetall: |
CommentIn: Nat Genet. 2016 Dec 28;49(1):2-3. - PMID 28029159 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2016 |
---|---|
Erschienen: |
2016 |
Enthalten in: |
Zur Gesamtaufnahme - volume:48 |
---|---|
Enthalten in: |
Nature genetics - 48(2016), 8 vom: 15. Aug., Seite 904-911 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Shin, Ha Youn [VerfasserIn] |
---|
Links: |
---|
Themen: |
Journal Article |
---|
Anmerkungen: |
Date Completed 07.09.2017 Date Revised 08.10.2019 published: Print-Electronic CommentIn: Nat Genet. 2016 Dec 28;49(1):2-3. - PMID 28029159 Citation Status MEDLINE |
---|
doi: |
10.1038/ng.3606 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM262040999 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM262040999 | ||
003 | DE-627 | ||
005 | 20231224200905.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231224s2016 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/ng.3606 |2 doi | |
028 | 5 | 2 | |a pubmed24n0873.xml |
035 | |a (DE-627)NLM262040999 | ||
035 | |a (NLM)27376239 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Shin, Ha Youn |e verfasserin |4 aut | |
245 | 1 | 0 | |a Hierarchy within the mammary STAT5-driven Wap super-enhancer |
264 | 1 | |c 2016 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 07.09.2017 | ||
500 | |a Date Revised 08.10.2019 | ||
500 | |a published: Print-Electronic | ||
500 | |a CommentIn: Nat Genet. 2016 Dec 28;49(1):2-3. - PMID 28029159 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Intramural | |
650 | 7 | |a Milk Proteins |2 NLM | |
650 | 7 | |a STAT5 Transcription Factor |2 NLM | |
650 | 7 | |a whey acidic proteins |2 NLM | |
700 | 1 | |a Willi, Michaela |e verfasserin |4 aut | |
700 | 1 | |a HyunYoo, Kyung |e verfasserin |4 aut | |
700 | 1 | |a Zeng, Xianke |e verfasserin |4 aut | |
700 | 1 | |a Wang, Chaochen |e verfasserin |4 aut | |
700 | 1 | |a Metser, Gil |e verfasserin |4 aut | |
700 | 1 | |a Hennighausen, Lothar |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature genetics |d 1992 |g 48(2016), 8 vom: 15. Aug., Seite 904-911 |w (DE-627)NLM012651230 |x 1546-1718 |7 nnns |
773 | 1 | 8 | |g volume:48 |g year:2016 |g number:8 |g day:15 |g month:08 |g pages:904-911 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/ng.3606 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 48 |j 2016 |e 8 |b 15 |c 08 |h 904-911 |