Molecular mechanisms regulating formation of diverse stem cell progenitors

摘要 干细胞前体细胞对胎儿和成人的健康至关重要。在哺乳动物中，第一批干细胞祖细胞是 受精后不久在胚胎中建立，为多能和胚外细胞类型。全能 细胞将成为胎儿，而胚外细胞将包围胎儿，并指导至关重要的 细胞类型包括心脏、血液和脑。未能正确执行第一个分子程序 因此，建立多能和胚外细胞类型可能会导致灾难性的发育结果。 我们的目标是理解这些分子程序。转录因子OCT4是已知的 小鼠胚胎中的多能细胞。有趣的是，我们发现OCT4还有第二个新的活动： 在胚胎中驱动胚胎外细胞的平行形成。值得注意的是，我们发现 常规体细胞同时诱导胚外干细胞和诱导多能干细胞 重新编程，表明重新编程比以前认识到的更能反映早期发展。 我们现在了解到，OCT4调节不同的转录靶点在多能性和 胚外细胞。然而，我们还不知道OCT4活性是如何调节的，以使其细胞类型- 特定功能。拟议研究的主要目标是发现OCT4活动是如何 在多能细胞和胚胎外细胞中的差异调节。我们将测试三个非独家型号 调节OCT4活性：细胞类型特异性OCT4结合伙伴、细胞类型特异性OCT4翻译后 修饰，以及细胞类型特定的染色质状态。由于独特的实验优势 在胚胎和重新编程的支持下，我们集成了各个模型系统中的研究，以使更快 比我们单独使用这两个系统都要进步。我们的方法将揭示新的分子机制 确保正常胚胎发育，确保重新编程期间可预测的结果，以及 依赖于OCT4的人类细胞类型的健康功能。我们的研究结果将影响临床 提高人类生育力，根除出生缺陷，设计创新的干细胞模型和 治疗。

ABSTRACT Stem cell progenitors are essential for fetal and adult wellness. In mammals, the first stem cell progenitors are established in the embryo shortly after fertilization, as pluripotent and extraembryonic cell types. Pluripotent cells will become the fetus, while extraembryonic cells will encircle the fetus and direct the formation of crucial cell types including heart, blood, and brain. The failure to properly execute the molecular programs that first establish pluripotent and extraembryonic cell types can thus result in catastrophic developmental outcomes. We aim to understand these molecular programs. The transcription factor OCT4 is known to be essential for pluripotent cells in the mouse embryo. Intriguingly, we discovered that OCT4 has a second, novel activity: driving the parallel formation of extraembryonic cells in the embryo. Remarkably, we discovered that extraembryonic stem cells are induced in parallel to induced pluripotent stem cells during routine somatic cell reprogramming, indicating that reprogramming mirrors early development more than previously appreciated. We now understand that OCT4 regulates the expression of distinct transcriptional targets in pluripotent and extraembryonic cells. However, we do not yet know how OCT4 activity is regulated to enable its cell type- specific functionalities. The prevailing goal of the proposed studies is to discover how OCT4 activity is differentially regulated in pluripotent and extraembryonic cells. We will test three non-exclusive models for modulating OCT4 activity: cell type-specific OCT4 binding partners, cell type-specific OCT4 post-translational modifications, and cell type-specific chromatin states. Because of the unique experimental advantages provided by embryos and reprogramming, we integrate studies in each model system to make more rapid progress than we could using either system alone. Our approach will expose new molecular mechanisms for ensuring normal embryonic development, for ensuring predictable outcomes during reprogramming, and for healthy functioning of human cell types that depend on OCT4. The outcomes of our studies will impact clinical goals of improving human fertility, eradicating birth defects, and devising innovative stem cell models and therapies.