Transcriptional Control of Stem Cell Fate.

Embryonic stem (ES) cells have two qualities that make them developmentally and clinically important: the ability to self-renew and the ability to differentiate into any embryonic cell type, or pluripotency. Understanding ES cell differentiation, and being able to control it, will be an important element in the realization of the enormous potential of stem cell medicine. We have shown that the NuRD co-repressor complex is essential for lineage commitment of pluripotent cells, and modulates gene expression levels to exert this function. This proposal exploits these findings to initiate an investigation into the regulation of transcription and differentiation in pluripotent cells. We will define how the enzymatic activities of NuRD component proteins influence transcriptional kinetics in pluripotent cells and upon lineage commitment. We will define how transcriptional heterogeneity of pluripotency genes is controlled at the molecular level, and define the role it plays in lineage commitm ent. We will identify genes and pathways instrumental in the initiation of lineage commitment by undertaking a genetic screen in our mutant ES cells to. Overall this proposal represents a strategic investigation into fundamental processes important for both basic developmental biology and for the future of stem cell medicine.