Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells.
Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells.
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DOI：
10.1016/j.molcel.2012.01.020
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发表时间：
2012-04-13
期刊：
影响因子：
16
通讯作者：
Huang J
中科院分区：
文献类型：
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作者：
Li M;He Y;Dubois W;Wu X;Shi J;Huang J
p53是调控胚胎干细胞和诱导多能干细胞（iPS）分化的关键基因。在这里，我们报告了小鼠胚胎干细胞中p53介导的DNA损伤信号的全基因组研究。系统分析显示p53在启动子区域的结合与基因激活显著相关，而与抑制无关。出乎意料的是，我们通过干扰远端增强子活性确定了p53介导的抑制的调控模式。重要的是，许多ES细胞富集的核心转录因子是p53抑制基因。进一步分析表明，p53抑制基因在功能上与ES/iPS细胞状态相关，而p53激活基因与分化相关。p53活化基因和p53抑制基因在表达水平和表观遗传标记上也表现出不同的特征。DNA损伤后，p53调节胚胎干细胞的自我更新和多能性。总之，这些结果支持了一个模型，即在DNA损伤的反应中，p53通过激活分化相关基因和抑制ES细胞富集基因来影响胚胎干细胞的状态。
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 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 that, in response to DNA damage, p53 affects the status of ES cells through activating differentiation-associated genes and repressing ES cell-enriched genes.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
21.3
作者：
Feng, Bo;Jiang, Jianming;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
DOI：
10.1073/pnas.0909734107
发表时间：
2010-01-05
影响因子：
11.1
作者：
Lee, Kyoung-Hwa;Li, Mangmang;Huang, Jing
通讯作者：
Huang, Jing
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
64.8
作者：
通讯作者：
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