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

Nat Commun. 2015 Mar 27:6:6520. doi: 10.1038/ncomms7520.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Long Noncoding
  • TP53 protein, human
  • Tumor Suppressor Protein p53

Associated data

  • GEO/GSE53499