Author(s):
Léveillé, Nicolas ; 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
Date: 2015
Persistent ID: https://hdl.handle.net/10316/109239
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): 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
Description
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.
