Léveillé, NicolasMelo, Carlos A.Rooijers, KoosDiaz-Lagares, AngelMelo, Sónia Rita Cardoso, 1978-Korkmaz, GozdeLopes, RuiAkbari Moqadam, FarhadMaia, Ana R.Wijchers, Patrick J.Geeven, Geertden Boer, Monique L.Kalluri, Raghude Laat, WouterEsteller, Manel, 1968-Agami, Reuven2018-10-242018-10-242015-03-272041-1723https://hdl.handle.net/2445/125594p53 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.application/pdfengcc-by (c) Léveillé, Nicolas et al., 2015http://creativecommons.org/licenses/by/3.0/esCàncerGenoma humàCancerHuman genomeinfo:eu-repo/semantics/article6626942018-10-24info:eu-repo/semantics/openAccess25813522