Abstract 2643: Regulation of stem cell differentiation by p53.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Differentiation is one of the barriers for tumorigenesis and reprogramming. In addition, embryonic stem (ES) and induced pluripotent stem (iPS) cells utilize differentiation to maintain their genomic stability by removing cells with mutation burden from the population in response to DNA damage. The tumor suppressor p53 is critical for regulating the differentiation of ES and iPS cells. However, the mechanism of how p53 regulates the differentiation of ES and iPS cells is unclear. To systematically study the underlying mechanisms, we employ an integrated genome-wide study in mouse ES cells. Systems analyses reveal that p53-activated genes and p53-repressed genes have distinct regulatory mechanisms and functions in mouse ES cells. Binding of p53 at promoter region significantly correlates with gene activation but not with repression. In addition, we unexpectedly identify a novel regulatory mode for p53-mediated repression through interfering with distal enhancer activity. This regulatory mode explains some but not all of the p53-mediated repressive events. Importantly, many ES cell-enriched core transcription factors are p53-repressed genes. Further analyses demonstrate that p53-repressed genes are functionally associated with ES and iPS cell status while p53-activated genes are linked to differentiation. Genome-wide analyses also show that p53-activated genes and -repressed genes have distinguishable features of expression levels and epigenetic markers, such as H3K4me3, H3K27me3 and H3K79me2. Upon DNA damage, p53 regulates the self-renewal and pluripotency of ES cells. Together, these results support a model that, in response to DNA damage, p53 affects the status of ES cells through activating differentiation-associated genes and repressing ES cell-enriched genes. Because many poorly differentiated tumors express ES-cell gene signature, our results may also have far-reaching implications in how p53 restricts the origin of cancer stem cells in adult tissues. Citation Format: Mangmang Li, Yunlong He, Wendy Dubois, Jing Huang. Regulation of stem cell differentiation by p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2643. doi:10.1158/1538-7445.AM2013-2643 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.