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 and Reuven Agami ()
Additional contact information
Nicolas Léveillé: The Netherlands Cancer Institute
Carlos A. Melo: The Netherlands Cancer Institute
Koos Rooijers: The Netherlands Cancer Institute
Angel Díaz-Lagares: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia 08908, Spain
Sonia A. Melo: University of Texas MD Anderson Cancer Center
Gozde Korkmaz: The Netherlands Cancer Institute
Rui Lopes: The Netherlands Cancer Institute
Farhad Akbari Moqadam: Erasmus University Medical Center, Erasmus MC
Ana R. Maia: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Patrick J. Wijchers: Hubrecht Institute-KNAW, University Medical Centre Utrecht
Geert Geeven: Hubrecht Institute-KNAW, University Medical Centre Utrecht
Monique L. den Boer: Erasmus University Medical Center, Erasmus MC
Raghu Kalluri: University of Texas MD Anderson Cancer Center
Wouter de Laat: Hubrecht Institute-KNAW, University Medical Centre Utrecht
Manel Esteller: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia 08908, Spain
Reuven Agami: The Netherlands Cancer Institute

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7520

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