Function of cell fate determinants during acquisition and loss of pluripotency

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Embryonic stem cells (ESCs), which are derived from the inner cell mass of mammalian blastocysts, have the ability to grow indefinitely while maintaining pluripotency and the ability to differentiate into cells of all three germ layers. Recent pioneering experiments have shown that by expressing four selected factors pluripotent cells can be generated from adult somatic cells. These cells are called induced pluripotent stem (iPS) cells. Interestingly, besides knowing which factors are necessary to achieve the reprogramming, it is rather unknown what molecular mechanisms regulate the “reprogrammability” of a somatic cell into an iPS cell. Furthermore, also the mechanisms and molecules that mediate the exit from pluripotency are poorly understood. Because both processes, reprogramming into iPS cells and exit from pluripotency, represent changes in cell fate we here propose the model that cell fate determinants are important regulators of these processes. Accordingly low levels of differentiation inducing cell fate determinants increase the potential of a cell to be reprogrammed into an induced pluripotent stem cell (iPS cell). In contrast the exit from pluripotency could be mediated by an upregulation of such determinants. We plan to address this hypothesis in detail by investigation of the function of the cell fate determinant TRIM32 during these processes. We have chosen to investigate TRIM32 in this context because of its expression pattern, its known direct regulation of the reprogramming factor c-Myc and its indirect, micro-RNA dependent regulation of the reprogramming factors Sox2, Nanog and Oct4. The successful completion of this project will lead to a more detailed understanding of the molecular mechanisms that regulate the entry and the exit into and from pluripotency. Additionally, this project could lead to methods to make induction of pluripotency as well as directed differentiation of pluripotent cells more efficient.