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 journalArticlepeer-review

144 Citations (Scopus)


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
Article number6520
JournalNature Communications
Publication statusPublished - Mar 2015
Externally publishedYes


  • Adenocarcinoma/genetics
  • Breast Neoplasms/genetics
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p21/genetics
  • DNA Methylation/genetics
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization, Fluorescence
  • MCF-7 Cells
  • Promoter Regions, Genetic
  • RNA, Long Noncoding/genetics
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Tumor Suppressor Protein p53/genetics


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