Investigation of the role if transriptional repression in cell fate decisions during mouse development. (360G-Wellcome-081816_B_06_A)

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 (pluripotency). A lot of effort has gone into defining molecular requirements of self-renewal, but little is known about how cells commit to differentiation and even less about how ES cells are derived. We have shown that the NuRD co-repressor complex required for the development of pluripotent cells in vivo and in potency of ES cells. This proposal builds on these findings to define the role of two major co-repressor complexes in derivation, potency and lineage commitment of pluripotent cells. We will identify epigenetic silencing events required for lineage commitment of pluripotent cells and define how silenced transcripts influence self-renewal, lineage commitment, and pluripotency. We will define molecularly the differences between ES cells and the embryonic cells from which they are derived and define the role played by epigenetic silencing in this process. We will biochemically define these complexes and identify their partners and targets in embryonic cells. Together this proposal comprises a molecular, biochemical, genetic and functional dissection of epigenetic silencing and cell fate decisions in pluripotent cells.