Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

Nicolas Léveillé, Carlos A Melo, Koos Rooijers, Angel Díaz-Lagares, Sonia A Melo, Gozde Korkmaz, Rui Lopes, Farhad Akbari Moqadam, Ana R Maia, Patrick J Wijchers, Geert Geeven, Monique L den Boer, Raghu Kalluri, Wouter de Laat, Manel Esteller, Reuven Agami

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6520
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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