RT Journal Article
SR Electronic
T1 Cell type-dependent control of p53 transcription and enhancer activity by p63
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 268649
DO 10.1101/268649
A1 Uzunbas, Gizem Karsli
A1 Ahmed, Faraz
A1 Sammons, Morgan A.
YR 2018
UL http://biorxiv.org/content/early/2018/08/30/268649.abstract
AB Transcriptional activation by p53 provides powerful, organism-wide tumor suppression. In this work, we demonstrate that the p53-induced transcriptome varies based on cell type, reflects cell type-specific activities, and is considerably more broad than previously anticipated. This behavior is strongly influenced by p53 engagement with differentially active cell type-specific enhancers and promoters. In epithelial cell types, p53 activity is dependent on the p53 family member p63, which displays widespread enhancer binding. Notably, we demonstrate that p63 is required for epithelial enhancer identity including enhancers used by p53 during stress-dependent signaling. Loss of p63, but not p53, leads to site-specific depletion of enhancer-associated chromatin modifications, suggesting that p63 functions as an enhancer maintenance factor in epithelial cells. Additionally, a subset of epithelial-specific enhancers is dependent on the activity of p63 providing a direct link between lineage determination and enhancer structure. These data suggest a broad, cell-intrinsic mechanism for regulating the p53-dependent cellular response to stress through differential regulation of cis-regulatory elements.