Critical POU domain residues confer Oct4 uniqueness in somatic cell reprogramming.
Critical POU domain residues confer Oct4 uniqueness in somatic cell reprogramming.
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关键的 POU 结构域残基赋予 Oct4 在体细胞重编程中的独特性。
DOI：
10.1038/srep20818
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发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Jin W;Wang L;Zhu F;Tan W;Lin W;Chen D;Sun Q;Xia Z
POU结构域转录因子Oct4在胚胎干细胞（ESCs）的自我更新和多能性中起关键作用。Oct4与Sox2、Klf4和c-Myc一起，可以重编程任何其他类型的细胞成为多能性，其中Oct4是唯一一个不能被其他POU家族成员在功能上取代的因子。为了研究Oct4基因独特性的决定因素，我们对小鼠Oct4基因的所有Ser、Thr、Tyr、Lys和Arg进行了Ala扫描，测试了它们在体细胞重编程中的能力。我们发现了一系列对Oct4功能很重要的残基，其中几乎所有这些关键残基都在POU结构域内，与DNA直接相互作用。Oct4的N端和c端转激活结构域（TAD）不是唯一的，可以被yes相关蛋白（YAP） TAD结构域取代以支持重编程。更重要的是，我们发现了在体细胞重编程中赋予Oct4独特性的两个重要残基。我们系统的结构-功能分析为关键残基如何共同作用赋予POU家族体细胞重编程Oct4独特性的分子基础提供了新的机制见解。
The POU domain transcription factor Oct4 plays critical roles in self-renewal and pluripotency of embryonic stem cells (ESCs). Together with Sox2, Klf4 and c-Myc, Oct4 can reprogram any other cell types to pluripotency, in which Oct4 is the only factor that cannot be functionally replaced by other POU family members. To investigate the determinant elements of Oct4 uniqueness, we performed Ala scan on all Ser, Thr, Tyr, Lys and Arg of murine Oct4 by testing their capability in somatic cell reprogramming. We uncovered a series of residues that are important for Oct4 functionality, in which almost all of these key residues are within the POU domains making direct interaction with DNA. The Oct4 N- and C-terminal transactivation domains (TADs) are not unique and could be replaced by the Yes-associated protein (YAP) TAD domain to support reprogramming. More importantly, we uncovered two important residues that confer Oct4 uniqueness in somatic cell reprogramming. Our systematic structure-function analyses bring novel mechanistic insight into the molecular basis of how critical residues function together to confer Oct4 uniqueness among POU family for somatic cell reprogramming.