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

描述(申请人提供)：植入前胚胎是胚胎干细胞的来源，因此为理解多能性的建立提供了一个独特的系统。转录因子Oct4(Pou5f1)和Sox2是ES细胞多能性所必需的，也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Sox2还有一个额外的作用：促进原始内胚层(PE)的分化，原始内胚层是一种重要的胚外组织。我们的数据支持这样一个模型，即Sox2非细胞自主地调节PE基因，而Oct4则细胞自主调节PE基因。Oct4和Sox2的基因靶点已经在干细胞的背景下被描述，但在胚胎中Oct4和Sox2的基因靶点尚不清楚。本研究的目的是了解Oct4和Sox2在胚胎中调控PE细胞命运的机制，确定Oct4和Sox2在胚胎和PE细胞中的靶点，并发现Oct4如何调控在一些细胞中诱导多能性基因，以及在胚胎的其他细胞中诱导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。这项研究有望影响干细胞研究，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有选择地促进或阻止干细胞和重编程期间PE分化的新方法。这项研究有望对生育研究产生影响，因为我们将确定胚外组织的新调节因子，这些调节因子对妊娠的建立和胎儿的健康发育至关重要。

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.