Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis

Cell Death Differ. 2012 Dec;19(12):1992-2002. doi: 10.1038/cdd.2012.89. Epub 2012 Jul 13.

Abstract

The tumor-suppressor p53 can induce various biological responses. Yet, it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using chromatin immunoprecipitation (ChIP)-seq revealed 'p53 default program', that is, the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, reactivation of p53 and induction of tumor cell apoptosis (RITA) or 5-fluorouracil in breast cancer cells, despite different biological outcomes. Parallel analysis of gene expression allowed identification of 280 novel p53 target genes, including p53-repressed AURKA. We identified Sp1 as one of the p53 modulators, which confer specificity to p53-mediated transcriptional response upon RITA. Further, we found that STAT3 antagonizes p53-mediated repression of a subset of genes, including AURKA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A
  • Aurora Kinases
  • Chromatin / metabolism*
  • Chromatin Immunoprecipitation
  • Chromosome Mapping
  • Furans / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome, Human*
  • HCT116 Cells
  • Humans
  • Imidazoles / pharmacology
  • MCF-7 Cells
  • Piperazines / pharmacology
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Response Elements
  • STAT3 Transcription Factor / metabolism
  • Sp1 Transcription Factor / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Chromatin
  • Furans
  • Imidazoles
  • NSC 652287
  • Piperazines
  • STAT3 Transcription Factor
  • Sp1 Transcription Factor
  • Tumor Suppressor Protein p53
  • nutlin 3
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases