Abstract
The p53 ability to elicit stress specific and cell type specific responses is well recognized, but how that specificity is established remains to be defined. Whether upon activation p53 binds to its genomic targets in a cell type and stress type dependent manner is still an open question. Here we show that the p53 binding to the human genome is selective and cell context-dependent. We mapped the genomic binding sites for the endogenous wild type p53 protein in the human cancer cell line HCT116 and compared them to those we previously determined in the normal cell line IMR90. We report distinct p53 genome-wide binding landscapes in two different cell lines, analyzed under the same treatment and experimental conditions, using the same ChIP-seq approach. This is evidence for cell context dependent p53 genomic binding. The observed differences affect the p53 binding sites distribution with respect to major genomic and epigenomic elements (promoter regions, CpG islands and repeats). We correlated the high-confidence p53 ChIP-seq peaks positions with the annotated human repeats (UCSC Human Genome Browser) and observed both common and cell line specific trends. In HCT116, the p53 binding was specifically enriched at LINE repeats, compared to IMR90 cells. The p53 genome-wide binding patterns in HCT116 and IMR90 likely reflect the different epigenetic landscapes in these two cell lines, resulting from cancer-associated changes (accumulated in HCT116) superimposed on tissue specific differences (HCT116 has epithelial, while IMR90 has mesenchymal origin). Our data support the model for p53 binding to the human genome in a highly selective manner, mobilizing distinct sets of genes, contributing to distinct pathways.
Highlights
Ever since the ability of the p53 tumor suppressor protein to bind DNA in a sequence-specific manner was established [1, 2], the specificity of p53 genomic binding has been intensively studied to gain insight into the network of p53 dependent target genes and their role in ensuring genomic protection and tumor suppression [3]
Because the overlap between the HCT116 and IMR90 p53 ChIP-seq peaks was due mainly to the IMR90 peaks out of CpG islands (CGIs) (Figure 2A), we examined separately the two IMR90 subsets: genes associated with peaks in CGIs, and genes associated with peaks out of CGIs
We reported distinct p53 genomic binding patterns based on analysis of data obtained by us in the normal human cell line IMR90 and by others in the cancer cell lines HCT116 and U2OS [16]
Summary
Ever since the ability of the p53 tumor suppressor protein to bind DNA in a sequence-specific manner was established [1, 2], the specificity of p53 genomic binding has been intensively studied to gain insight into the network of p53 dependent target genes and their role in ensuring genomic protection and tumor suppression [3]. We reported significant differences between the genome-wide distributions of the p53 binding sites we mapped in normal human fibroblasts [16] and those identified by others in human cancer cell lines [8, 11, 12]. Direct comparison and interpretation of differences between non-coordinated genome-wide studies is challenging when experimental variations are considered (e.g. cell types, treatment conditions, and sequencing approaches). We mapped de novo the p53 binding sites in the cancer cell line HCT116, applying the same treatment (6 hrs, 5-FU), approach (ChIP-seq) and analysis pipeline, used for our IMR90 study. That the p53 binding sites reside in distinct genomic landscapes in the HCT116 and IMR90 cell lines, under the same experimental conditions. That result confirms p53 binding to the genome in a cell context-dependent manner
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