Auxin-degron system identifies immediate mechanisms of OCT4.
Auxin-degron system identifies immediate mechanisms of OCT4.
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DOI：
10.1016/j.stemcr.2021.05.016
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发表时间：
2021-07-13
影响因子：
5.9
通讯作者：
Silva JCR
中科院分区：
文献类型：
--
作者：
Bates LE;Alves MRP;Silva JCR
多能性因子OCT 4对于维持幼稚多能干细胞在体外和体内是必不可少的。然而，OCT 4在这一过程中的具体作用仍然未知。在这里，我们开发了一种快速的蛋白质水平的OCT 4消耗系统，证明了对OCT 4损失的直接下游反应是关键多能性因子的表达减少。我们的数据显示，OCT 4的几个关键的多能性因子的有效转录的要求，并表明滋养外胚层标记物的表达是一个后续事件。此外，我们发现NANOG能够在没有OCT 4的情况下与基因组结合，并且这种结合实际上是增强的。然而，在全球范围内，活性增强子相关的组蛋白标记H3K27ac被耗尽。我们的工作确定，虽然OCT 4是维持幼稚转录因子网络所必需的，但在正常胚胎干细胞水平，它通过抑制NANOG结合来拮抗该网络。OCT 4是关键多能性基因的增强子活性和转录所必需的在OCT 4缺失时退出多能性先于滋养外胚层基因表达NANOG能够在OCT 4不存在的情况下结合基因组OCT 4降低NANOG结合基因组的能力在这篇文章中，Silva及其同事表明，对小鼠nPSC中OCT4缺失的最初反应是关键多能性基因的表观遗传和转录沉默，随后是滋养外胚层相关基因的表达。此外，他们证明NANOG保持其与基因组结合的能力，并且在不存在OCT 4的情况下增强。
The pluripotency factor OCT4 is essential for the maintenance of naive pluripotent stem cells in vitro and in vivo. However, the specific role of OCT4 in this process remains unknown. Here, we developed a rapid protein-level OCT4 depletion system that demonstrates that the immediate downstream response to loss of OCT4 is reduced expression of key pluripotency factors. Our data show a requirement for OCT4 for the efficient transcription of several key pluripotency factors and suggest that expression of trophectoderm markers is a subsequent event. In addition, we find that NANOG is able to bind to the genome in the absence of OCT4, and this binding is in fact enhanced. Globally, however, the active enhancer-associated histone mark H3K27ac is depleted. Our work establishes that, while OCT4 is required for the maintenance of the naive transcription factor network, at a normal embryonic stem cell levels it antagonizes this network through inhibition of NANOG binding. OCT4 is required for enhancer activity and transcription of key pluripotency genes Exit from pluripotency precedes trophectoderm gene expression on loss of OCT4 NANOG is able to bind to the genome in the absence of OCT4 OCT4 reduces the capacity of NANOG to bind to the genome In this article, Silva and colleagues show that the initial response to the loss of OCT4 in mouse nPSCs is epigenetic and transcriptional silencing of key pluripotency genes, followed by the expression of trophectoderm-associated genes. Furthermore, they demonstrate that NANOG maintains its capacity to bind to the genome, and this is enhanced in the absence of OCT4.
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影响因子：
64.5
作者：
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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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影响因子：
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作者：
Matoba, Ryo;Niwa, Hitoshi;Masui, Shinji;Ohtsuka, Satoshi;Carter, Mark G.;Sharov, Alexei A.;Ko, Minoru S. H.
通讯作者：
Ko, Minoru S. H.
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Miyazaki, J