Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation.
Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation.
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DOI：
10.1002/stem.1532
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发表时间：
2014-01
期刊：
影响因子：
5.2
通讯作者：
Xu, Yang
中科院分区：
文献类型：
--
作者：
Zhang, Zhen-Ning;Chung, Sun-Ku;Xu, Zheng;Xu, Yang
Oct4对维持人类胚胎干细胞（hESC）的多能性至关重要，然而，其潜在机制仍有待充分理解。在这里，我们报告说，沉默的Oct4在hESC中导致肿瘤抑制p53的激活，诱导hESC的分化，因为p53条件性敲除（p53CKO）hESC中p53的急性破坏阻止hESC的分化后Oct4耗尽。我们进一步发现，Oct4的沉默显著降低了Sirt1的表达，Sirt1是一种已知抑制p53活性和ESC分化的脱乙酰酶，导致p53在赖氨酸120和164处的乙酰化增加。Sirt1在介导Oct4依赖性多能性中的重要性通过发现Sirt1在Oct4沉默的hESC中的异位表达阻止p53活化和hESC分化而揭示。此外，采用敲入方法，我们揭示了p53在赖氨酸120和164处的乙酰化对于p53在hESC中的稳定和活性都是必需的。总之，我们的研究结果揭示了Oct4通过抑制诱导分化的途径在维持hESC多能性方面的新作用。考虑到p53抑制胚胎干细胞DNA损伤反应后的多能性，我们的研究结果进一步强调了协调DNA损伤反应途径和多能性途径以维持hESC的多能性和基因组稳定性的严格机制。
Oct4 is critical to maintain the pluripotency of human embryonic stem cells (hESCs), however, the underlying mechanism remains to be fully understood. Here we report that silencing of Oct4 in hESCs leads to the activation of tumor suppressor p53, inducing the differentiation of hESCs since acute disruption of p53 in p53 conditional knockout (p53CKO) hESCs prevents the differentiation of hESCs after Oct4 depletion. We further discovered that the silencing of Oct4 significantly reduces the expression of Sirt1, a deacetylase known to inhibit p53 activity and the differentiation of ESCs, leading to increased acetylation of p53 at lysine 120 and 164. The importance of Sirt1 in mediating Oct4-dependent pluripotency is revealed by the finding that the ectopic expression of Sirt1 in Oct4-silenced hESCs prevents p53 activation and hESC differentiation. In addition, employing knock-in approach, we revealed that the acetylation of p53 at lysine 120 and 164 is required for both stabilization and activity of p53 in hESCs. In summary, our findings reveal a novel role of Oct4 in maintaining the pluripotency of hESCs by suppressing pathways that induce differentiation. Considering that p53 suppresses pluripotency after DNA damage response in ESCs, our findings further underscore the stringent mechanism to coordinate DNA damage response pathways and pluripotency pathways in order to maintain the pluripotency and genomic stability of hESCs.
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影响因子：
9.8
作者：
Jain AK;Allton K;Iacovino M;Mahen E;Milczarek RJ;Zwaka TP;Kyba M;Barton MC
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通讯作者：
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影响因子：
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通讯作者：
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