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

• Autor(a) principal: Léveillé, Nicolas
• Data de Publicação: 2015
• Outros Autores: Melo, Carlos A., Rooijers, Koos, Díaz-Lagares, Angel, Melo, Sonia A., Korkmaz, Gozde, Lopes, Rui, Moqadam, Farhad Akbari, Maia, Ana R, Wijchers, Patrick J., Geeven, Geert, den Boer, Monique L., Kalluri, Raghu, de Laat, Wouter, Esteller, Manel, Agami, Reuven
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/109239; https://doi.org/10.1038/ncomms7520
• topic: Adenocarcinoma; Breast Neoplasms; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase Inhibitor p21; DNA Methylation; Enhancer Elements, Genetic; Female; Humans; In Situ Hybridization, Fluorescence; MCF-7 Cells; Promoter Regions, Genetic; RNA, Long Noncoding; Real-Time Polymerase Chain Reaction; Sequence Analysis, RNA; Tumor Suppressor Protein p53; Gene Expression Regulation, Neoplastic

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.