Transcription factor dynamics in control of pluripotent cell function and identity

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Stem cells attract considerable attention because of their potential to repair damaged or exhausted tissue in patients. There are two properties that define stem cells and that account for their potential utility. First, stem cells can make identical copies of themselves and can do this indefinitely, a process we call self-renewal. Second, stem cells can change their properties and become a specialised type of cell that carries out a particular function in our bodies. Within an organism these two properties of self-renewal and specialisation must be balanced. If too many cells specialise, then the stem cell population may run out. If too many cells self-renew, there may be an insufficient supply of specialised cells to maintain an organisms functionality. How does an organism meet these demands upon its stem cell population? We believe we have uncovered an explanation and want to explore the detailed mechanisms behind our observations. We study a type of stem cell called an embryonic stem (or ES) cell. We study mouse ES cells because they are the most tractable experimentally. We found that all cells in an ES cell population are not the same; some have a greater likelihood of specialising and others a greater likelihood of self-renewing. Unexpectedly we found that these two states could interconvert and the cells that were more likely to specialise could still self-renew and move back into a more niave state. Crucially we were able to determine that these two states could be distinguished by the presence or absence of a particular gene regulator, Nanog. In the proposed work, we will ask how Nanog interacts with other gene regulators throughout the genome to turn genes on or off. We will identify genes that carry out the functions of Nanog. A major part of our work will be to determine the mechanisms that switch the Nanog gene on and off and that are therefore central to the function of the stem cell. We will relate our studies to stem cells from more mature embryos and test the relevance of our findings to the intact embryo.Our studies will deliver a deeper understanding of the switches controlling the behaviour of ES cells. Not only will this be important in learning how to optimally apply ES cells in potentially therapeutic situations but may provide fundamental insights applicable to all stem cells.