Transcriptional and epigenetic determinants of the epithelial-mesenchymal transition

身体每个组织中的每种细胞类型都有与其特定功能相关的独特身份。无论细胞类型是干细胞还是神经元、肌肉或皮肤细胞，该细胞的独特身份主要是通过一组独特基因的表达来建立的。然而，对于一些细胞来说，它们的身份具有相当大的灵活性（可塑性），使它们能够根据环境线索改变形状和行为。这些转变通常是特定于环境的，但越来越多的证据表明，在经历类似变化的不同细胞类型之间存在某些共性。一个显著的例子是上皮细胞到间质细胞的转化，简称EMT。******EMT是一种表型开关，上皮细胞失去定义特征，如细胞极性和稳定的细胞间连接，并向间充质状态过渡，能够迁移和组织侵袭。它对许多生物过程至关重要，包括胚胎原肠形成、心脏发育、纤维化和伤口愈合。除了增加细胞的迁移能力外，驱动EMT的分子程序还可以激活分化上皮细胞中的干细胞样表型。这种状态之间的转换是高度动态的，是由复杂的分子网络精心策划的。人们认为，细胞通过连续的轨迹经历EMT转变，在具有不同特征和稳定程度的中间状态中旅行。除了上皮或间充质状态的标志性分子标记外，对这些状态的定义特征或它们之间的转换知之甚少。如果我们要了解其转录和表观遗传决定因素及其动力学，EMT的复杂性需要广泛，深入的分析，这是我们的目标。******我们计划从一个简单的模型系统开始，用TGFB1处理卵巢上皮细胞，TGFB1是一个因其诱导EMT的能力而被公认的因子。我们的目标是在静态和动态细胞模型中使用高通量基因组学和功能丧失方法探索核小体组织和转录输出之间的关系。从长远来看，通过探索来自其他组织的上皮细胞的这一过程以及对其他环境线索的反应，我们希望能够辨别出可推广的调节原则，这将提高我们对细胞状态如何维持以及状态之间如何发生转变的理解。公开访问后，这些数据将成为进一步数据挖掘的主要资源，用于探索涉及伤口修复和其他EMT介导的细胞过程的机制，定义导致成体干细胞状态的特定途径，并为当前部分或可逆EMT的数学模型提供信息。

Each cell type in every tissue of the body has a unique identity associated with its particular function. Whether the cell type is a stem cell or a neuron, muscle or skin cell, the unique identity of that cell is mainly established by the expression of a unique set of genes. For some cells, however, their identity has considerable flexibility (plasticity) that allows them to change their shape and behavior as they respond to environmental cues. These transitions are normally context-specific, but there is growing evidence for certain commonalities among different cell types undergoing similar changes. A notable example is called the epithelial-to-mesenchymal transition, or EMT.******EMT is a phenotypic switch where epithelial cells lose defining characteristics, such as cell polarity and stable cell-to-cell junctions, and transition towards a mesenchymal state, capable of migration and tissue invasion. It is critical for many biological processes including embryo gastrulation, heart development, fibrosis, and wound healing. In addition to increasing a cell's capacity for migration, the molecular program driving the EMT can also activate a stem cell-like phenotype in differentiated epithelial cells. ***This transition between states is highly dynamic and is orchestrated by complex molecular networks. It is thought that cells undergoing an EMT transition through a continuous trajectory, travelling through intermediate states with varying characteristics and degrees of stability. Beyond hallmark molecular markers of the epithelial or mesenchymal state, relatively little is known about the defining features of these states or the transitions between them. The complexity of the EMT requires an extensive, in-depth analysis if we are to understand its transcriptional and epigenetic determinants, and their kinetics, which is our goal.******We plan to start with a simple model system ovarian epithelial cells treated with TGFB1, a factor well-established for its ability to induce the EMT. We aim to explore the relationship between nucleosome organization and transcriptional output using high-throughput genomics, and loss-of-function approaches in both static and dynamic cellular models. In the long-term, by exploring this process in epithelial cells from other tissues and in response to other environmental cues, we hope to discern generalizable regulatory principles that will improve our understanding of how cell state is maintained, and how transitions between states occur. Made publicly accessible, the data will be a major resource for further data mining, to explore mechanisms involved in wound repair and other EMT-mediated cellular processes, to define specific pathways that contribute to the adult stem cell state, and to inform current mathematical models of partial or reversible EMT.