Transcription factor dynamics in control of pluripotent cell function and identity

干细胞因其修复患者受损或衰竭组织的潜力而引起相当大的关注。有两种特性定义了干细胞，并解释了它们潜在的效用。首先，干细胞可以复制相同的自身，并且可以无限复制，我们称之为自我更新。其次，干细胞可以改变它们的特性，成为一种特殊类型的细胞，在我们的身体中执行特定的功能。在一个有机体中，自我更新和专业化这两种特性必须得到平衡。如果太多的细胞特化，那么干细胞群可能会耗尽。如果太多的细胞自我更新，可能会有专门的细胞供应不足，以维持生物体的功能。生物体如何满足对其干细胞群的这些需求？我们相信我们已经发现了一个解释，并希望探索我们观察背后的详细机制。我们研究一种叫做胚胎干细胞（ES）的干细胞。我们研究小鼠胚胎干细胞是因为它们在实验上是最容易处理的。我们发现胚胎干细胞群体中的所有细胞都不一样；一些人更有可能专业化，而另一些人更有可能自我更新。出乎意料的是，我们发现这两种状态可以相互转换，更有可能特殊化的细胞仍然可以自我更新，并回到一个更简单的状态。至关重要的是，我们能够确定这两种状态可以通过一种特定基因调节因子Nanog的存在或缺失来区分。在提议的工作中，我们将询问Nanog如何与整个基因组中的其他基因调节因子相互作用以打开或关闭基因。我们将确定执行Nanog功能的基因。我们工作的一个主要部分将是确定开启和关闭Nanog基因的机制，因此这对干细胞的功能至关重要。我们将把我们的研究与来自更成熟胚胎的干细胞联系起来，并测试我们的发现与完整胚胎的相关性。我们的研究将对控制胚胎干细胞行为的开关提供更深入的理解。这不仅对学习如何在潜在的治疗情况下最佳地应用胚胎干细胞很重要，而且可能提供适用于所有干细胞的基本见解。

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.