期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7520
关键词
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资金
- Fundacao para a Ciencia e a Tecnologia, Portugal [SFRH/BD/33472/2008, SFRH/BD/74476/2010]
- Human Frontiers Program
- Netherlands Organization for Scientific Research ('NWO' Vidi grant)
- ISCIII at the Spanish Ministry of Economy and Competitiveness [CD12/00738]
- European Research Council (ERC) [268626]
- ICREA Funding Source: Custom
- Fundação para a Ciência e a Tecnologia [SFRH/BD/74476/2010, SFRH/BD/33472/2008] Funding Source: FCT
p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer.
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