A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response

Oncogene. 2016 Aug 18;35(33):4399-406. doi: 10.1038/onc.2015.502. Epub 2016 Jan 18.

Abstract

Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Enhancer Elements, Genetic / physiology*
  • G1 Phase Cell Cycle Checkpoints
  • Humans
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism
  • RNA, Long Noncoding / physiology*
  • Tumor Suppressor Protein p53 / physiology*

Substances

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