OTX2 impedes self-renewal of porcine iPS cells through downregulation of NANOG expression.
OTX2 impedes self-renewal of porcine iPS cells through downregulation of NANOG expression.
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DOI：
10.1038/cddiscovery.2016.90
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发表时间：
2016
影响因子：
7
通讯作者：
Wang, Huayan
中科院分区：
文献类型：
--
作者：
Wang, Ning;Wang, Yaxian;Xie, Youlong;Wang, Huayan
转录因子Otx2在小鼠多能干细胞从原始多能性向引物多能性转变的调控中起负开关作用。然而，猪OTX2在猪诱导多能干细胞（piPSCs）中的分子特征和功能尚未得到很好的阐明。通过研究高通量转录组测序和干扰内源性OTX2表达，我们证明OTX2能够降低pipsc的自我更新。OTX2在猪脑、生殖组织和着床前胚胎中高度表达，但在成纤维细胞和大多数体细胞组织中检测不到。然而，先前报道的已知piPSC系根据诱导程序和培养条件产生不同水平的OTX2。过表达猪OTX2可降低碱性磷酸酶阳性菌落的百分比，下调NANOG和OCT4的表达。而敲低OTX2可显著增加内源性NANOG、OCT4和ESRRB的表达，稳定pipsc的多能状态。另一方面，如ChIP-seq数据所示，NANOG可以直接结合OTX2启动子，并以剂量依赖的方式抑制OTX2启动子活性。这些结果表明，OTX2和NANOG可以形成负反馈回路来调节猪iPS细胞的多能性。
The transcription factor Otx2 acts as a negative switch in the regulation of transition from naive to primed pluripotency in mouse pluripotent stem cells. However, the molecular features and function of porcine OTX2 have not been well elucidated in porcine-induced pluripotent stem cells (piPSCs). By studying high-throughput transcriptome sequencing and interfering endogenous OTX2 expression, we demonstrate that OTX2 is able to downgrade the self-renewal of piPSCs. OTX2 is highly expressed in porcine brain, reproductive tissues, and preimplantation embryos, but is undetectable in fibroblasts and most somatic tissues. However, the known piPSC lines reported previously produced different levels of OTX2 depending on the induction procedures and culture conditions. Overexpression of porcine OTX2 can reduce the percentage of alkaline phosphatase-positive colonies and downregulate NANOG and OCT4 expression. In contrast, knockdown of OTX2 can significantly increase endogenous expressions of NANOG, OCT4, and ESRRB, and stabilize the pluripotent state of piPSCs. On the other hand, NANOG can directly bind to the OTX2 promoter as shown in ChIP-seq data and repress OTX2 promoter activity in a dose-dependent manner. These observations indicate that OTX2 and NANOG can form a negative feedback circuitry to regulate the pluripotency of porcine iPS cells.
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影响因子：
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