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Search for target genes of STAT3 that maintains pluripotency of embryonic stem cells

寻找维持胚胎干细胞多能性的STAT3靶基因

基本信息

批准号：
12680669
负责人：
KOIDE Hiroshi
金额：
$ 2.5万
依托单位：
Graduate School of Medical Science, Kanazawa University (2001)The University of Tokyo (2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

STAT3 is a transcriptional factor that is involved in self-renewal of embryonic stem (ES) cells. To identify target genes of STAT3 in the self-renewal, we searched for a gene(s) that shows higher expression in undifferentiated ES cells than in differentiated ES cells by using subtraction method and DNA microarray, and found several candidate genes. Of them, we focused our attention on the following two genes.1. zinc-finger protein (zfp) 57 Oct-3/4, a pluripotent stem cell-specific transcription factor, plays a critical role in the self-renewal of ES cells. Several evidences suggest that gene expression via Oct-3/4 requires an unidentified co-factor(s). We found that Zfp57 is expressed during the self-renewal of ES cells, while its expression is reduced upon differentiation. By co-immunoprecipitation assay, it was also found that Zfp57 interacts with Oct-3/4. Furthermore, Zfp57 enhanced the transcriptional activity of Oct-3/4 towards the promoter of rex-1, an Oct-3/4 target gene, in hum … More an embryonic kidney 293 cells. Our data suggest that Zfp57, a target of STAT3, is one of the Oct-3/4 co-factors, and raise the possibility that this protein may cooperate with Oct-3/4 in induction of Rex-1, which in turn may play an important role in the self-renewal of ES cells.2. Embryonic ectoderm development (eed) Recent studies revealed that gene expression is tightly associated with acetylation of histone, which is controlled by histone acetyltransferases and histpne deacylases (HDACs). Bed, a member of the polycomb family, is known to bind with HDAC. We found that Bed is one of the downstream molecules of STATS. Treatment of ES cells with trichostatin A, an HDAC inhibitor, led to the initiation of differentiation, suggesting that histone acetylation is involved in regulation of the self-renewal. Interestingly, we found that Bed forms a complex also with Rex-1. Since deacylation ofhistone generally results in repression of gene expression, these results suggest the possibility that the Eed・Rex-1・HDAC complex may maintain the undifferentiated state of ES cells by suppressing the expression of a differentiation-inducing gene(s). Less

STAT3是一种参与胚胎干细胞自我更新的转录因子。为了确定STAT3在自我更新中的靶基因，我们利用减法和DNA微阵列技术寻找了一个在未分化ES细胞中表达高于分化ES细胞的基因，并找到了几个候选基因。其中，我们重点关注了以下两个基因。锌指蛋白（zfp） 57 Oct-3/4是一种多能干细胞特异性转录因子，在胚胎干细胞的自我更新中起着关键作用。一些证据表明，通过Oct-3/4进行的基因表达需要一个未知的辅助因子。我们发现Zfp57在ES细胞的自我更新过程中表达，而在分化过程中表达减少。通过共免疫沉淀实验，还发现Zfp57与Oct-3/4相互作用。Zfp57在胚胎肾293细胞中增强了Oct-3/4对Oct-3/4靶基因rex-1启动子的转录活性。我们的数据表明STAT3的靶点Zfp57是Oct-3/4的辅助因子之一，并提出该蛋白可能与Oct-3/4协同诱导Rex-1，进而在ES细胞的自我更新中发挥重要作用。胚胎外胚层发育（eed）近年来的研究表明，基因表达与组蛋白乙酰化密切相关，而组蛋白乙酰化受组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDACs）的控制。Bed是polycomb家族的一员，已知与HDAC结合。我们发现Bed是STATS的下游分子之一。用HDAC抑制剂trichostatin A处理胚胎干细胞，导致分化开始，这表明组蛋白乙酰化参与了自我更新的调节。有趣的是，我们发现Bed也与Rex-1形成复合体。由于组蛋白的去酰化通常会导致基因表达的抑制，这些结果表明，Eed·Rex-1·HDAC复合体可能通过抑制分化诱导基因的表达来维持胚胎干细胞的未分化状态。少