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Access Type
WSU Access
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
First Advisor
Lori L. Pile
Abstract
SIN3 is a constitutive regulator that controls metabolic genes and pathways by effecting the post translational modification profile of histone tails. SIN3 directly binds and regulates many genes that encode enzymes in central carbon metabolism. Furthermore, SIN3 regulates the metabolites in central carbon metabolism, indicating that SIN3 regulation on metabolic genes affects the bioenergetics of cells. I explored the cross talk between metabolites and epigenetic regulation, and the impact of acetyl-CoA and SAM on gene expression and epigenetic regulators in Chapter 1. Since SIN3 plays a significant role in central carbon metabolism, we hypothesized that SIN3 is also required for the cellular response to changes to metabolic flux. We found that SIN3 regulation on some central carbon metabolism genes is affected by glycolytic inhibition. Measurement of cellular bioenergetics revealed that SIN3 is required for the cellular response to changes to mitochondrial and glycolytic flux. Additionally, the SIN3 complex composition was measured and was unaffected by glycolytic inhibition. This proteomic approach, however, allowed us to gain insights into how SIN3 might regulate genes through interacting with accessory proteins. This study is described in Chapter 2. In Drosophila, Sin3A is differentially spliced and produces two major SIN3 isoforms, SIN3 220 and SIN3 187. Bioinformatic analysis of publicly available data allowed me to identify potential mechanism in which the SIN3 isoforms regulates genes, which I present in Chapter 3. I parsed genes that were activated and repressed by the isoforms and measured the histone modification profile and the binding of RNA pol II of those genes. We found that SIN3 regulation of genes might involve modulation of RNA pol II binding, possibly though pausing factors. By analyzing the levels in which SIN3 regulates genes, we were able to support our hypothesis that SIN3 regulates genes through a soft-regulation manner, by fine-tuning the expression of genes and not by hard-regulation manner, wherein genes are turned on or off. In summary, the studies presented here aim to provide insight into the role SIN3 plays in bioenergetic regulation, and the mechanism in which SIN3 regulates genes
Recommended Citation
Soukar, Imad, "Elucidating The Role And Action Of The Epigenetic Regulator Sin3: Focus On Metabolism" (2023). Wayne State University Dissertations. 3914.
https://digitalcommons.wayne.edu/oa_dissertations/3914