title: Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells.
abstract: 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.
authors.affiliation: Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Mangmang
authors.initials: M
authors.lastname: Li
authors.forename: Yunlong
authors.initials: Y
authors.lastname: He
authors.forename: Wendy
authors.initials: W
authors.lastname: Dubois
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D051379:Mice; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53