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

SWI/SNF亚基在人胚胎干细胞增强子调控中的作用

• 批准号: 9154868
• 负责人: Lee Frank Langer
• 金额: --
• 依托单位: U.S. NATIONAL INST OF ENVIRON HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9154868
• 关键词: ATP phosphohydrolase; Address; Affect; Binding; Brain; Catalytic Domain; Cell physiology; Cells; Cessation of life; Characteristics; Clinical Treatment; Complex; Computer Simulation; DNA; DNA Polymerase II; Data; Decision Making; Developmental Gene; Enhancers; Event; Exhibits; Fingers; Gene Targeting; Genes; Genetic Transcription; Hepatocyte; Human Genome; Laboratories; Machine Learning; Modeling; Mus; Myocardial Infarction; Nucleosomes; Parkinson Disease; Positioning Attribute; Process; Property; Proteins; Protocols documentation; RNA; Regulation; Role; SMARCA4 gene; SMARCB1 gene; SMARCC1 gene; Stem cells; Sucrose; Testing; Therapeutic; Thinking; Training; Transcription Initiation Site; Untranslated RNA; Work; abstracting; base; cell type; chromatin remodeling; design; human embryonic stem cell; human stem cells; knock-down; pluripotency; protein complex; self-renewal; small hairpin RNA; stem; stem cell differentiation; stem cell therapy; transcription factor

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.

项目总结/摘要 人类干细胞有能力或“潜能”转化为体内任何类型的细胞（Noggle，et al. 2005）。 因为许多疾病或事件，如帕金森病和心脏病发作，其特征是 特定细胞类型的损伤或死亡，可能使用干细胞来治疗这些疾病 （Edlinger，2015; Pantcheva等人，2015）。然而，有很多关于干细胞的事情需要 在取得这些进展之前，我们已经了解了，这个项目解决了关于干细胞如何 转化成其他细胞类型。 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如何转化 从一种细胞类型转移到另一种细胞类型。我们知道这个过程的一个主要部分是不同的基因， 控制细胞功能的DNA是活跃的，不活跃的，或者介于两者之间。我们也知道 一个基因是活跃的还是不活跃的取决于DNA中被称为增强子的其他片段， 调光器开关决定基因的活性（Kaikkonen等人，2013）。尽管我们知道增强子调节 基因，我们不完全了解增强子本身是如何调节的。 细胞中有一组分子或蛋白质复合物，它们在增强子上起作用，就像手指上的手指。 调光开关，改变增强子激活或失活基因的程度（Hu，2011）。其中一 复合物被称为SWI/SNF复合物。SWI/SNF复合物如何靶向特异性增强子，以及 它是如何使增强子或多或少地激活基因的，这在很大程度上是一个悬而未决的问题。什么让 更复杂的问题是复合物的特定组分并不总是相同的（Wang，et al. 1996年）。我们的实验室认为，组成SWI/SNF复合物的特定蛋白质有助于将其靶向某些特定的蛋白质。 增强子并影响增强子是否导致其调节的基因更活跃或更不活跃。 如果我们能了解增强子是如何受到SWI/SNF复合物的影响，我们将有更好的 了解细胞如何激活和失活某些基因，从而了解干细胞如何能够 变成了一种细胞类型而不是另一种。因此，本提案的目的如下： 目的1：检测SWI/SNF复合物的不同组分是否差异调节人干细胞 增强剂。 目的2：确定SWI/SNF组分在调节增强子特性中的特定作用， 它们或多或少可能调节基因活性。 目的3：设计一个计算模型来预测增强子是如何被 SWI/SNF复合体。