Molecular Cell
Volume 46, Issue 1, 13 April 2012, Pages 30-42
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Article
Distinct Regulatory Mechanisms and Functions for p53-Activated and p53-Repressed DNA Damage Response Genes in Embryonic Stem Cells

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Summary

p53 is critical in regulating the differentiation of ES and induced pluripotent stem (iPS) cells. Here, we report a whole-genome study of p53-mediated DNA damage signaling in mouse ES cells. Systems analyses reveal that binding of p53 at the promoter region significantly correlates with gene activation but not with repression. Unexpectedly, we identify a regulatory mode for p53-mediated repression through interfering with distal enhancer activity. Importantly, many ES cell-enriched core transcription factors are p53-repressed genes. Further analyses demonstrate that p53-repressed genes are functionally associated with ES/iPS cell status while p53-activated genes are linked to differentiation. p53-activated genes and -repressed genes also display distinguishable features of expression levels and epigenetic markers. Upon DNA damage, p53 regulates the self-renewal and pluripotency of ES cells. Together, these results support a model where, in response to DNA damage, p53 affects the status of ES cells through activating differentiation-associated genes and repressing ES cell-enriched genes.

Highlights

► p53 represses many core transcription factors in ES cells ► Genome-wide p53 binding at the promoter region correlates with activation ► Interference with distal enhancers is a paradigm for p53-mediated repression ► p53 activates differentiation-linked genes and represses stem cell genes

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