Galvagni Federico, Lentucci Claudia, Neri Francesco, Dettori Daniela, De Clemente Caterina, Orlandini Maurizio, Anselmi Francesca, Rapelli Stefania, Grillo Michela, Borghi Sara, Oliviero Salvatore
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy.
Stem Cells. 2015 Mar;33(3):742-50. doi: 10.1002/stem.1898.
Although much is known about the pluripotency self-renewal circuitry, the molecular events that lead embryonic stem cells (ESCs) exit from pluripotency and begin differentiation are largely unknown. We found that the zinc finger transcription factor Snai1, involved in gastrulation and epithelial-mesenchymal transition, is already expressed in the inner cell mass of the preimplantation blastocysts. In ESCs, Snai1 does not respond to TGFβ or BMP4 signaling but it is induced by retinoic acid treatment, which induces the binding, on the Snai1 promoter, of the retinoid receptors RARγ and RXRα, the dissociation of the Polycomb repressor complex 2 which results in the decrease of H3K27me3, and the increase of histone H3K4me3. Snai1 mediates the repression of pluripotency genes by binding directly to the promoters of Nanog, Nr5a2, Tcl1, c-Kit, and Tcfcp2l1. The transient activation of Snai1 in embryoid bodies induces the expression of the markers of all three germ layers. These results suggest that Snai1 is a key factor that triggers ESCs exit from the pluripotency state and initiate their differentiation processes.
尽管我们对多能性自我更新回路已有很多了解，但导致胚胎干细胞（ESC）退出多能性并开始分化的分子事件在很大程度上仍不清楚。我们发现，参与原肠胚形成和上皮 - 间充质转化的锌指转录因子Snai1在植入前囊胚的内细胞团中就已表达。在胚胎干细胞中，Snai1对TGFβ或BMP4信号不产生反应，但视黄酸处理可诱导其表达，视黄酸处理会导致类视黄醇受体RARγ和RXRα与Snai1启动子结合，多梳抑制复合物2解离，从而导致H3K27me3减少以及组蛋白H3K4me3增加。Snai1通过直接结合Nanog、Nr5a2、Tcl1、c - Kit和Tcfcp2l1的启动子来介导多能性基因的抑制。在胚状体中短暂激活Snai1会诱导所有三个胚层标志物的表达。这些结果表明，Snai1是触发胚胎干细胞退出多能性状态并启动其分化过程的关键因子。
