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

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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.