Identification of universal and cell type specific p53 DNA binding

Abstract

The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell type specific gene expression programs, however recent studies and meta-analyses of genomic data propose largely uniform, and condition independent, p53 binding. To systematically assess the cell type specificity of p53, we measured its association with DNA in 12 p53 wildtype cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. These results position p53 as having both universal and cell type specific regulatory programs that have different regulators and dependence on chromatin state.

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

“…These results corroborated that pTINCR is upregulated upon stress in a p53 dependent manner. We analyzed published p53 ChIP-seq experiments 60,61 and we did not observe p53 binding to pTINCR locus, either in control cells or in cells treated with DNA-damaging agents, suggesting that the regulation of pTINCR by p53 is indirect (Supplementary Fig. 5E, F).…”

Control of p53-dependent transcription and enhancer activity by the p53 family member p63

“…The most straightforward potential mechanism driving our observation of cell type-dependent transcriptional activation by p53 involves differential binding of p53 to regulatory regions controlling those genes. Recent analyses reached opposing conclusions with regard to the cell type-dependence of p53 engagement with the genome (3,25,27,28). We therefore assessed whether differences in p53 engagement with the genome in our model cell lines might explain our observations of cell type-dependent transcriptomes.…”

“…A recent set of meta-analyses has suggested that p53 binding to the genome is invariant (25), proposing that p53 acts independently to drive gene expression of a core tumor suppressor network across all cell types due to the low enrichment of other transcription factor motifs at p53-bound enhancers and the reported pioneer factor activity of p53 (3,25,26). Conversely, a series of recent p53 ChIP-seq experiments observed cell type-specific p53 binding and gene targets (27,28). Because of the high importance of these conflicting observations and the mutual exclusivity of the models, additional experimental evidence and models are required to unravel these disparate p53 regulatory mechanisms.…”

Cell differentiation modifies the p53 transcriptional program through a combination of gene silencing and constitutive transactivation

“…Targeted pharmacological inhibition of the MDM2-p53 interaction is being tested in cancer therapy, with several small molecule inhibitors already developed, such as the first-in-class compound Nutlin-3 [18]. Although these molecules specifically activate p53 and its downstream target genes, they elicit highly diverse responses across cell types [4,19]. In most cancer cell types the response to MDM2 inhibition is a reversible form of cell cycle arrest of little therapeutic value, with only few cell lines undergoing apoptosis [4].…”