Molecular mechanisms regulating formation of diverse stem cell progenitors

摘要 干细胞祖细胞对胎儿和成人的健康至关重要。在哺乳动物中，第一个干细胞祖细胞是 在受精后不久在胚胎中建立，作为多能和胚外细胞类型。多能 细胞将成为胎儿，而胚外细胞将包围胎儿，并直接形成关键的细胞。 包括心脏、血液和大脑的细胞类型。未能正确执行分子程序， 因此，建立多能和胚外细胞类型可导致灾难性的发育结果。 我们的目标是了解这些分子程序。已知转录因子OCT 4对于 小鼠胚胎中的多能细胞。有趣的是，我们发现OCT 4有第二个新的活性： 驱动胚胎中胚外细胞的平行形成。值得注意的是，我们发现， 在常规体细胞培养过程中，胚胎外干细胞与诱导多能干细胞平行诱导， 重新编程，表明重新编程反映了早期发展比以前认识到的。 我们现在了解到，OCT 4调节多能和多能细胞中不同转录靶点的表达， 胚外细胞然而，我们还不知道OCT 4活性是如何调节的，以使其细胞类型- 具体功能。拟议研究的主要目标是发现OCT 4活性是如何影响 在多能和胚外细胞中差异调节。我们将测试三个非排他性模型， 调节OCT 4活性：细胞类型特异性OCT 4结合配偶体，细胞类型特异性OCT 4翻译后 修饰和细胞类型特异性染色质状态。由于独特的实验优势 通过胚胎和重编程提供，我们整合了每个模型系统中的研究， 比单独使用任何一个系统都要进步。我们的方法将揭示新的分子机制， 确保正常的胚胎发育，确保在重编程期间的可预测结果，以及 依赖于OCT 4的人类细胞类型的健康功能。我们的研究结果将影响临床 提高人类生育能力，消除出生缺陷，设计创新的干细胞模型， 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.