Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo

Abstract

The tumor suppressor p53 is a transcription factor that coordinates the cellular response to DNA damage. Here we provide an integrated analysis of p53 genomic occupancy and p53-dependent gene regulation in the splenic B and non-B cell compartments of mice exposed to whole-body ionizing radiation, providing insight into general principles of p53 activity in vivo. In unstressed conditions, p53 bound few genomic targets; induction of p53 by ionizing radiation increased the number of p53 bound sites, leading to highly overlapping profiles in the different cell types. Comparison of these profiles with chromatin features in unstressed B cells revealed that, upon activation, p53 localized at active promoters, distal enhancers, and a smaller set of unmarked distal regions. At promoters, recognition of the canonical p53 motif as well as binding strength were associated with p53-dependent transcriptional activation, but not repression, indicating that the latter was most likely indirect. p53-activated targets constituted the core of a cell type-independent response, superimposed onto a cell type-specific program. Core response genes included most of the known p53-regulated genes, as well as many new ones. Our data represent a unique characterization of the p53-regulated response to ionizing radiation in vivo.

Genome-wide analysis of p53-regulated transcription in Myc-driven lymphomas

“…Virtually all p53 binding sites identified here in lymphomas were present in normal mouse B cells after in vivo irradiation 18 (Supplementary Figure S9a). Hence, given the same cellular context, p53 bound a common set of sites irrespective of the type of stimulus.…”

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

“…Based on previously published ChIP sequencing analysis (Mateo et al, 2015; Mehta et al, 2011; Tonelli et al, 2015), we identified two putative p53 binding sites at the Wnt7b locus near the transcription start site and ~50 kb upstream, and one Olig2 binding site ~30 kb upstream of the Wnt7b locus (Figure 3A). Loss of Olig2 function resulted in significantly higher p53 occupancy at the Wnt7b locus; conversely, in Trp53 −/− cells, Olig2 binding was enriched (Figures 3B and 3C).…”

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

“…1b). Notably, among the WT p53 targets identified in recent transcriptomic and ChIP-seq studies carried out in various cell models there are no proteasome-ubiquitylation pathway genes shared with our integrated or common mutant p53 signatures [23][24][25][26] .…”