PhD Projects on offer
Dissecting the molecular mechanisms of extraembryonic endoderm differentiation
Supervisor: Dr. Kathy Niakan
Transcription factors function to regulate gene expression and the modulation of these factors can direct the differentiation of stem cells to differentiated cells and revert differentiated cells back to stem cells. Oct4, Nanog, and Sox2 form the core of a transcription factor network that promotes embryonic stem cell (ESC) pluripotency and self-renewal while simultaneously repressing genes required for differentiation. Although the function of the Oct4/Nanog/Sox2 network in promoting pluripotency is well described, how other transcription factors act to disrupt it and induce differentiation is poorly understood. We seek to define the molecular hierarchy that acts during the transdifferentiation of extraembryonic endoderm (XEN) cells from ESCs. We have established inducible ESCs for endoderm transcription factors. These inducible cell lines will be used to test the sufficiency of the transcription factors to drive XEN cell transdifferentiation. Time-course analysis of gene and protein expression changes following transcription factor overexpression will allow us to determine the order of molecular events during the differentiation process and to address why some transcription factors fail to induce a XEN cell switch. These will form the basis of future hypotheses about the role of specific genes in driving XEN cell lineage restriction and may ultimately facilitate our efforts to direct differentiation towards therapeutically relevant cells to model and treat diseases.
This project will address the following questions: Which molecular mechanisms are involved in embryonic stem cell to extraembryonic endoderm differentiation? How does stem cell state and signaling influence lineage decisions? Are there conserved mechanisms in human and mouse extraembryonic differentiation?
