生物
增强子
等级制度
计算生物学
状态5
遗传学
细胞生物学
转录因子
信号转导
基因
经济
市场经济
作者
Ha Youn Shin,Michaela Willi,Kyung Hyun Yoo,Xianke Zeng,Chaochen Wang,Gil Metser,Lothar Hennighausen
出处
期刊:Nature Genetics
[Springer Nature]
日期:2016-07-04
卷期号:48 (8): 904-911
被引量:229
摘要
Lothar Hennighausen and colleagues identify 440 mammary-specific super-enhancers in mouse and focus on the STAT5-regulated Wap gene. Genetic dissection of the Wap super-enhancer suggests an internal hierarchy, as mutations in one of the constituent enhancers incapacitate the entire regulatory region. 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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