Molecular mechanisms regulating formation of diverse stem cell progenitors

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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.