Pluripotent stem cells possess the dual defining properties of self-renewal and multi-lineage differentiation potential. To retain an effective differentiation capacity, self-renewal must occur at high efficiency. Self-renewal is controlled by the action of sequence specific DNA binding transcription factors (TFs), with the TF NANOG showing a direct correlation between concentration and self-renewal efficiency (Chambers et al. 2003, 2007). However, the mechanisms by which pluripotency TFs communicate to the biochemical machinery that makes RNA is surprisingly poorly understood. In new work, our lab has shown that NANOG directly contacts the large subunit of RNA Polymerase II (RNAP2), through the RNAP2 C-terminal domain (CTD). This interaction can by dissociated by CDK9, the enzyme that causes release of RNAP2 from pause sites downstream of the transcription start site. This project will take multiple in-cell and in vitro approaches to examine the interactions of RNAP2 and NANOG with specific chromatin sites. In addition, the effects of expression of additional NANOG interacting proteins on the interaction of NANOG with RNAP2 will be assessed. This project will deliver a fuller understanding of how NANOG interacts with partner proteins to drive transcriptional change.
The student will receive training to become proficient in biochemical analysis of transcription factor function, analytical molecular biology, confocal microscopy, genome editing and cell culture. The student will be provided with development opportunities to enable them to fully exploit their results as well as having access to transferable skills training. http://www.crm.ed.ac.uk/research/group/embryonic-stem-cell-biology
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Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S. and Smith, A. G. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in mouseembryonic stem cells. Cell 113, 643-655
Chambers, I., Silva, J., Colby, D., Nichols, J., Robertson, M., Nijmeijer, B., Vrana, J., Jones, K., Grotewold, L. and Smith, A. (2007) Nanog safeguards pluripotency and mediates germ cell development. Nature, 450, 1230-1234.