Abstract PR01: Genome wide profiling reveals stimulus-specific functions of p53 in human embryonic stem cells

Abstract

Abstract p53 is a critical guardian of somatic cells in the face of cellular stress and genomic challenges. Recent work shows that functions of transcription factor p53 go beyond its well-studied roles in tumor suppression. In addition to functions in cell cycle arrest and apoptosis, p53 is a functional barrier to reprogramming adult cells into induced pluripotent (iPS) cells that are phenotypically similar to embryonic stem (ES) cells. How p53 is regulated and functions in stem cells, is poorly understood. Previously we have shown that p53 plays a significant role that depends on its transcriptional activity in early differentiation of human ES cells (hESCs), as induced in vitro by retinoic acid (RA). In order to delineate p53 transcriptional functions during differentiation and how p53 selectively responds to specific signals in hESCs we performed genome wide profiling of p53 chromatin interactions and target gene expression in hESCs in response to early differentiation or DNA damage. The majority of p53 binding sites is unique to each state and defines stimulus-specific p53 response in hESCs. p53 binding regions specific to differentiation significantly overlap with those of core-pluripotency factors OCT4 and NANOG. Differentiation-specific p53 targets are highly expressed, and include many developmental transcription factors, poised by OCT4/NANOG and bivalent histone marks (H3K4me3 and H3K27me3) in pluripotent hESCs. Activation of poised genes during differentiation is associated with elimination of H3K27me3 marks, which is largely dependent on p53. During hESC differentiation, p53 interacts with H3K37me3 specific de-methylases (JMJD3 and UTX) that are enriched at the upstream regions of poised genes resulting in alteration of bivalent histone status and subsequent gene activation. These studies suggest that p53 plays essential roles in regulating epigenetic bivalency in ES cells. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in cell death and cell cycle regulation are conserved in both DNA damage and differentiation. Thus, our findings expand the registry of p53-regulated genes to define p53-mediated opposition to pluripotency during early differentiation, a process highly distinct from stress-induced p53 response in hESCs. This abstract is also presented as poster A68. Citation Format: Abhinav K. Jain, Kadir C. Akdemir, Kendra Allton, Bruce Aronow, Xueping Xu, Austin J. Cooney, Wei Li, Michelle C. Barton. Genome wide profiling reveals stimulus-specific functions of p53 in human embryonic stem cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR01.