Revealing a human p53 universe

Abstract

Abstractp53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.

Diepoxybutane induces the expression of a novel p53‐target gene XCL1 that mediates apoptosis in exposed human lymphoblasts

“…In summary, we have demonstrated for the first time that XCL1 is a novel direct p53 target gene mediating apoptosis in DEB‐exposed human lymphoblasts. These findings contribute to understanding p53 signaling in DEB‐induced apoptosis and toxicity [30,40] . These findings also expand the current knowledge base surrounding the relationship between p53 function and diverse stresses, as expressed through its target genes [40] .…”

“…Genome‐wide p53 binding and transactivation landscapes are differentially affected by diverse stresses, including DNA damage [28,39] . Thus, these reports explain why exogenously expressed wild‐type p53 transactivated the XCL1 promoter in DEB‐exposed cells but not in unexposed cells, and why novel p53 target genes are continuously being discovered [29,30] . The experimental strategies utilized to determine that XCL1 is a novel direct p53 transcriptional target gene have been utilized by others to identify novel p53 target genes PinX1, fractalkine, NCF2, and CSF1 [14,15] .…”

“…We report for the first time that the XCL1 gene‐mediated DEB‐induced apoptosis in exposed human lymphoblasts. Exogeneous XCL1 and XCL1 upregulating BFA and PSK were reported to induce apoptosis in various cell systems [27–31,38,40] . The relationship between XCL1 upregulation and the p53 status in these systems was not investigated.…”

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

“…6A as open rectangle) contains a p53 ChIP-Seq peak (p53 binding site identified by sequencing of chromatin immunoprecipitated with anti-p53 antibody). The presence of the peak, located on chromosome 11, positions: 119,037,091-119,037,351 (genome version hg19) was reported in meta-analysis performed by Nguyen et al [32]. The p53 ChIP-Seq peaks identified by others in this region and publically available through ChIP-Atlas tool [33] are visualized in supplementary Fig.…”

“…Thus, the cloned DNA sequence of NLRP1 gene responds only to wild-type p53, but the location of the major p53 RE is not known. The aforementioned meta-analysis of the location of p53 ChIP-Seq peaks [32] may shed light on the mechanism of p53 binding to NLRP1 promoter, which contains p53 ChIP-Seq peak located in positions 5,487,941 to 5,488,641 of on chromosome 17 (genome version hg19, marked by open rectangle on Fig. 6A and visualized in supplementary Fig.…”