The roles of SWI/SNF subunits in human embryonic stem cell enhancer regulation

项目摘要/摘要 人类干细胞具有转化为体内任何类型细胞的能力或“潜能”(Nogger等人)。2005)。 因为许多情况或事件，如帕金森氏症和心脏病发作，都具有 特定细胞类型的损伤或死亡，有可能使用干细胞来治疗这些疾病 (Edlinger，2015；Pantcheva，等人。2015年)。然而，有很多关于干细胞的事情需要 在取得这些进展之前被理解，这个项目解决了干细胞是如何 转化为其他类型的细胞。 实现干细胞疗法的全部力量的一个主要障碍是了解干细胞是如何转化的 从一种细胞类型转变为另一种细胞类型。我们知道这个过程的一个主要部分是不同的基因，你的部分 控制细胞功能的DNA是活跃的、非活跃的，或者介于两者之间。我们也知道， 基因的活性或非活性取决于DNA的其他片段，称为增强子，它们的作用类似于 Dimmer会改变基因的活性(Kaikkonen等人)。2013)。尽管我们知道增强剂能调节 基因，我们并不完全了解增强剂本身是如何被调控的。 在细胞中有一组分子，或蛋白质复合体，起到增强剂的作用，就像手指上的 调光开关，改变增强子激活或失活基因的程度(Hu，2011)。这其中的一个 复合体被称为SWI/SNF复合体。SWI/SNF复合体如何针对特定的增强剂，以及 它如何使增强剂或多或少有可能激活基因，在很大程度上是悬而未决的问题。是什么让这个 更复杂的问题是，复合体的具体组成部分并不总是相同的(Wang，et 艾尔1996年)。我们的实验室认为，组成SWI/SNF复合体的特定蛋白质有助于将其靶向某些 增强并影响增强子是否导致其调控的基因更活跃或更不活跃。 如果我们能够了解增强剂是如何受到SWI/SNF复合体的影响的，我们就会有一个更好的 了解细胞如何激活和失活某些基因，从而了解干细胞是如何 变成了一种细胞类型而不是另一种细胞类型。因此，这项建议的目的如下： 目的1：测试SWI/SNF复合体的不同成分是否对人类干细胞有不同的调节作用 增强剂。 目的2：确定SWI/SNF组件在调节增强子特性中的特定作用 它们或多或少都有可能调节基因活动。 目标3：设计一个计算模型来预测增强剂是以什么方式受以下成分调控的 特种部队/特种部队综合体。

Project Summary/Abstract Human stem cells have the power, or “potency” to turn into any type of cell in the body (Noggle, et al. 2005). Because many conditions or events, such as Parkinson's disease and heart attacks, are characterized by damage to or death of specific cell types, it may be possible to use stem cells to treat these conditions (Edlinger, 2015; Pantcheva, et al. 2015). However, there is a great deal about stem cells that needs to be understood before these advances can be made, and this project addresses questions about how stem cells turn into other cell types. One major hurdle in achieving the full power of stem cell therapies is to understand how stem cells transition from one cell type into another. We know that a major part of this process is that different genes, parts of your DNA that control how a cell functions, are active, inactive, or somewhere in between. We also know that whether a gene is active or inactive depends on other segments of the DNA called enhancers, which act like dimmer switches for how active a gene is (Kaikkonen, et al. 2013). Although we know that enhancers regulate genes, we do not completely understand how enhancers themselves are regulated. There are groups of molecules, or protein complexes, in the cell that function at enhancers like the finger on a dimmer switch, changing how much an enhancer activates or inactivates a gene (Hu, 2011). One of these complexes is referred to as the SWI/SNF complex. How the SWI/SNF complex targets specific enhancers, and how it makes enhancers more or less likely to activate a gene, are largely open questions. What makes the problem more complicated is that the specific components of the complex are not always the same (Wang, et al. 1996). Our lab thinks that the specific proteins that make up the SWI/SNF complex help target it to certain enhancers and affects whether the enhancer causes the gene it regulates to be more or less active. If we can understand how enhancers are affected by the SWI/SNF complex, we will have a better understanding of how a cell activates and inactivates certain genes and therefore how stem cells can be changed into one cell type versus another. Therefore, the aims of this proposal are as follows: Aim 1: Test whether the different components of the SWI/SNF complex differentially regulate human stem cell enhancers. Aim 2: Determine the specific roles of SWI/SNF components in regulating enhancer characteristics that make them more or less likely to regulate gene activity. Aim 3: Design a computational model to predict in what way enhancers are regulated by the components of the SWI/SNF complex.