title: Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.
abstract: 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.
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Kristina
authors: K
authors: Kirschner
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Shamith A
authors: SA
authors: Samarajiwa
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Jonathan M
authors: JM
authors: Cairns
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Suraj
authors: S
authors: Menon
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Pedro A
authors: PA
authors: Pérez-Mancera
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Kosuke
authors: K
authors: Tomimatsu
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Camino
authors: C
authors: Bermejo-Rodriguez
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Yoko
authors: Y
authors: Ito
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Tamir
authors: T
authors: Chandra
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Masako
authors: M
authors: Narita
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Scott K
authors: SK
authors: Lyons
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Andy G
authors: AG
authors: Lynch
authors: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors: Hiroshi
authors: H
authors: Kimura
authors: Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors: Tetsuya
authors: T
authors: Ohbayashi
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Simon
authors: S
authors: Tavaré
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors: Masashi
authors: M
authors: Narita
mesh_terms: D000375:Aging / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D018899:CpG Islands / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D010641:Phenotype; D060066:Protein Interaction Maps / Q000235:genetics*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D013230:Stearoyl-CoA Desaturase