Journal Article

Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53

Pérez-Mancera, Pedro A., Chandra, Tamir, Lynch, Andy G., Bermejo-Rodriguez, Camino, Cairns, Jonathan M., Menon, Suraj, Samarajiwa, Shamith A., Lyons, Scott K., Ito, Yoko, Ohbayashi, Tetsuya, Tavaré, Simon, Narita, Masako, Tomimatsu, Kosuke, Narita, Masashi, Kirschner, Kristina, Kimura, Hiroshi

2015

Overview

The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aging - genetics / Apoptosis / Apoptosis - genetics / Cancer / Cell cycle / Cell Line / Chronic illnesses / CpG Islands - genetics / Deoxyribonucleic acid / DNA / DNA binding proteins / DNA damage / DNA Damage - genetics / DNA Methylation - genetics / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enzymes / Gene expression / Gene Expression Regulation / Genes, Tumor Suppressor / Genetic regulation / Genomes / Genomics / Genotype & phenotype / Humans / Identification and classification / Islands / Mutation / Phenotype / Phenotypes / Physiological aspects / Protein Interaction Maps - genetics / Senescence / Stearoyl-CoA Desaturase - genetics / Stearoyl-CoA Desaturase - metabolism / Transcription factors / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism