Changing POU dimerization preferences converts Oct6 into a pluripotency inducer.
Changing POU dimerization preferences converts Oct6 into a pluripotency inducer.
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改变 POU 二聚化偏好将 Oct6 转化为多能诱导剂
DOI：
10.15252/embr.201642958
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发表时间：
2017-02
期刊：
影响因子：
7.7
通讯作者：
Jauch R
中科院分区：
文献类型：
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作者：
Jerabek S;Ng CK;Wu G;Arauzo-Bravo MJ;Kim KP;Esch D;Malik V;Chen Y;Velychko S;MacCarthy CM;Yang X;Cojocaru V;Schöler HR;Jauch R
转录因子Oct 4是诱导多能干细胞（iPSC）的分子鸡尾酒的核心成分，而POU家族的其他成员不能以相当的效率取代Oct 4。相反，III组POU因子如Oct 6诱导神经谱系。在这里，我们试图确定决定Oct 4和Oct 6的差异DNA结合和重编程活性的分子特征。在多能性基因的增强子中，Oct 4与Sox 2在异源二聚体SoxOct元件上协作。通过重新分析ChIP-Seq数据和进行二聚化测定，我们发现Oct 6在回文OctOct上的同源二聚化比Oct 4更协同和更稳定。使用结构和生化分析，我们确定了一个单一的氨基酸指导结合到各自的DNA元件。这种氨基酸的变化降低了Oct 4产生iPSC的能力，而Oct 6中的回复突变不会增加其重编程活性。然而，通过两个额外的氨基酸交换，Oct 6获得了产生iPSC并保持多能性的能力。总之，我们证明了细胞类型特异性POU因子功能是由影响DNA依赖性二聚化的选择残基决定的。
The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA‐binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re‐analyzing ChIP‐Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type‐specific POU factor function is determined by select residues that affect DNA‐dependent dimerization.