Molecular Regulation of Cell Fate in Stem Cells and Early Mouse Embryos

描述（由申请人提供）：植入前胚胎是胚胎干（ES）细胞的来源，因此提供了一个独特的系统来了解多能性的建立。转录因子Oct4（Pou5f1）和Sox 2是ES细胞中多能性所必需的，并且是诱导多能性的关键调节因子。我们的证据表明，在小鼠胚胎中，Oct4和Sox 2具有额外的作用：促进原始内胚层（PE）的分化，这是一种必需的胚外组织。我们的数据支持一个模型，其中Sox2调节PE基因非细胞自主，和Oct4调节PE基因细胞自主。Oct4和Sox 2的基因靶标已经在干细胞背景下描述，但Oct4和Sox 2在胚胎中的基因靶标是未知的。本研究的目的是解决Oct4和Sox 2调节胚胎中PE细胞命运的机制，确定Oct4和Sox 2在胚胎和PE细胞中的靶点，并发现Oct4如何调节以诱导某些细胞中的多能性基因和胚胎其他细胞中的PE基因。为了实现这些目标，我们将整合经典胚胎学和现代基因组学方法。这项研究预计将影响干细胞研究，因为了解如何调节Oct4在促进多能性和PE分化方面的双重作用将揭示选择性促进或预防干细胞和重编程过程中PE分化的新方法。这项研究预计将影响生育研究，因为我们将确定胚胎外组织的新调节因子，这对建立怀孕和健康的胎儿发育至关重要。

DESCRIPTION (provided by applicant): The preimplantation embryo is the source of embryonic stem (ES) cells, and therefore provides a unique sys- tem in which to understand the establishment of pluripotency. The transcription factors Oct4 (Pou5f1) and Sox2 are necessary for pluripotency in ES cells and are key regulators of induced pluripotency. Our evidence indicates that in the mouse embryo, Oct4 and Sox2 have an additional role: promoting differentiation of the primitive endoderm (PE), an essential extraembryonic tissue. Our data support a model wherein Sox2 regulates PE genes non cell-autonomously, and Oct4 regulates PE genes cell-autonomously. The gene targets of Oct4 and Sox2 have been described in the stem cell context, but the gene targets of Oct4 and Sox2 in the embryo are unknown. The objectives of this study are to resolve the mechanisms by which Oct4 and Sox2 regulate PE cell fate in the embryo, to identify the targets of Oct4 and Sox2 in the embryo and in PE cells, and to discover how Oct4 is regulated to induce pluripotency genes in some cells, and PE genes in other cells of the embryo. To achieve these goals, we will integrate classical embryological and modern genomic approaches. This study is expected to impact stem cell research, because understanding how to regulate dual roles of Oct4 in promoting pluripotency and PE differentiation will reveal new ways to selectively promote or prevent PE differentiation in stem cells and during reprogramming. This study is expected to impact fertility research be- cause we will identify new regulators of extraembryonic tissues, which are essential for establishment of pregnancy and healthy fetal development.