Transcriptional and epigenetic determinants of the epithelial-mesenchymal transition

上皮-间质转化的转录和表观遗传决定因素

• 批准号: RGPIN-2018-06538
• 负责人: Vanderhyden, Barbara
• 金额: $ 3.06万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667590
• 关键词: Transcriptional; epigenetic; determinants; epithelial; mesenchymal

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.

身体每种组织中的每种细胞类型都具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，对于某些细胞来说，它们的身份具有相当大的灵活性（可塑性），使它们能够在响应环境线索时改变它们的形状和行为。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。一个值得注意的例子是所谓的上皮间质转化，或EMT。EMT是一种表型开关，其中上皮细胞失去定义特征，如细胞极性和稳定的细胞间连接，并向间充质状态转变，能够迁移和组织侵入。它对许多生物过程至关重要，包括胚胎原肠胚形成，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的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，并由复杂的分子网络协调。据认为，经历EMT转变的细胞通过连续的轨迹，通过具有不同特征和稳定程度的中间状态行进。除了上皮或间充质状态的标志性分子标志物之外，对这些状态的定义特征或它们之间的转换知之甚少。EMT的复杂性需要一个广泛的，深入的分析，如果我们要了解它的转录和表观遗传决定因素，以及它们的动力学，这是我们的目标。我们计划从一个简单的模型系统开始-用TGFB 1处理的卵巢上皮细胞，TGFB 1是一种因其诱导EMT的能力而建立的因子。我们的目标是使用高通量基因组学以及静态和动态细胞模型中的功能丧失方法来探索核小体组织和转录输出之间的关系。从长远来看，通过在其他组织的上皮细胞中探索这一过程以及对其他环境线索的反应，我们希望能够发现可推广的调控原则，这些原则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换的理解。这些数据将成为进一步数据挖掘的主要资源，以探索伤口修复和其他EMT介导的细胞过程中涉及的机制，定义有助于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。