TP53 engagement with the genome occurs in distinct local chromatin environments via pioneer factor activity
- ↵* Corresponding author; email: bergers{at}mail.med.upenn.edu
Abstract
Despite overwhelming evidence that transcriptional activation by p53 is critical for its tumor suppressive activity, the mechanisms by which p53 engages the genome in the context of chromatin to activate transcription are not well understood. Using a compendium of novel and existing genome-wide datasets, we examined the relationship between p53 binding and the dynamics of the local chromatin environment. Our analysis revealed three distinct categories of p53 binding events that differ based on the dynamics of the local chromatin environment. The first class of p53 binding events occur near transcriptional start sites (TSS) and are defined by previously-characterized promoter-associated chromatin modifications. The second class comprises a large cohort of pre-established, promoter-distal enhancer elements that demonstrate dynamic histone acetylation and transcription upon p53 binding. The third class of p53 binding sites are devoid of classic chromatin modifications and, remarkably, fall within regions of inaccessible chromatin, suggesting that p53 has intrinsic pioneer factor activity and binds within structurally inaccessible regions of chromatin. Intriguingly, these inaccessible p53 binding sites feature several enhancer-like properties in cell types within the epithelial lineage, indicating that p53 binding events include a group of 'proto-enhancers' that become active enhancers given the appropriate cellular context. These data indicate that p53, along with p63, may act as pioneer factors to specify epithelial enhancers. Further, these findings suggest that, rather than following a global cell-type invariant stress response program, p53 may tune its response based on the lineage-specific epigenomic landscape.
- Received July 21, 2014.
- Accepted November 12, 2014.
- Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
