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EFFECTS of POSTTRANSLATIONAL MODIFICATION of TRANSCRIPTION FACTOR GLI-SIMILAR 3 by SUMOYLATION on INSULIN TRANSCRIPTION in PANCREATIC Β CELLS Tyler M

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EFFECTS of POSTTRANSLATIONAL MODIFICATION of TRANSCRIPTION FACTOR GLI-SIMILAR 3 by SUMOYLATION on INSULIN TRANSCRIPTION in PANCREATIC Β CELLS Tyler M Murray State's Digital Commons Murray State Theses and Dissertations Graduate School 2017 EFFECTS OF POSTTRANSLATIONAL MODIFICATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 BY SUMOYLATION ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS Tyler M. Hoard Murray State University Follow this and additional works at: https://digitalcommons.murraystate.edu/etd Part of the Cell Biology Commons, and the Molecular Genetics Commons Recommended Citation Hoard, Tyler M., "EFFECTS OF POSTTRANSLATIONAL MODIFICATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 BY SUMOYLATION ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS" (2017). Murray State Theses and Dissertations. 56. https://digitalcommons.murraystate.edu/etd/56 This Thesis is brought to you for free and open access by the Graduate School at Murray State's Digital Commons. It has been accepted for inclusion in Murray State Theses and Dissertations by an authorized administrator of Murray State's Digital Commons. For more information, please contact [email protected]. EFFECTS OF SUMOYLATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS A Thesis Presented to The Faculty of the Department of Biological Sciences Murray State University Murray, Kentucky In Partial Fulfillment of the Requirements for the Degree of Master of Science in Biology By Tyler Matthew Hoard December 2017 iii Acknowledgements There are so many people to whom I am thankful for the roles that they have played in the completion of this project. I would first like to thank my thesis advisor, Dr. Gary ZeRuth. His guidance, patience, troubleshooting suggestions, and devotion to carrying out impactful research have contributed significantly to preparing me for a future in biomedical research. I would also like to thank my thesis committee members, Dr. Ed Zimmerer, Dr. Chris Trzepacz, Dr. David Canning, and Dr. J. Ricky Cox for dedicating their time and providing additional guidance and suggestions. Dr. Dayle Saar has been a valuable source of advice and support, and for that I am grateful. Additionally, I am thankful for the opportunities that have been provided to me by the Murray State Department of Biological Sciences. My appreciation for my fellow ZeRuth lab researchers, Dylan Hammrich, Katie Alexander, Fumi Nakamura, and Erin Clayton, whom I have been able to depend on to be a constant source of lively company that has proven to be particularly valuable on long days of work and to help with experiments, cannot be overstated. I am also thankful for all of the staff in the Biology Department Office for being a dependable source for whimsical conversation and unlimited coffee on particularly stressful days. This effort would have been virtually impossible without the unwavering support of my family. They have always taken a significant interest in my aspirations, and I owe a large portion of my success in this journey to them. Finally, I would like to thank my friends Jon Dunning, Jordan Osman, and Ashley Munie for providing countless instances of enjoyment and relaxation as well as providing feedback on much of this work. iv This research was supported by NSF-KY EPSCoR grant [RSF-042-14] and the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health [Z01-ES-100485] with additional support from a competitive research grant sponsored by the Committee for Institutional Studies and Research at Murray State University v Abstract The ability to control blood glucose levels is a fundamental component of vertebrates. In these organisms, blood glucose homeostasis is achieved through a fine- tuned mechanism that largely involves the secretion of hormones from the endocrine pancreas into the bloodstream. These hormones include glucagon, which is secreted by the α cells of the pancreas and initiates the release of glucose into the bloodstream through gluconeogenesis in the liver, and insulin, which is secreted from the β cells and signals the uptake of excess blood glucose by the peripheral tissue. Gli-similar 3 (Glis3) is a transcription factor that has previously been shown to play a critical role in both the development of β cells and transcriptional activation of the insulin gene. The mechanism by which the activity of Glis3 is modulated is still largely enigmatic. The posttranslational modification of proteins by covalent attachment of the small ubiquitin-like modifier protein (SUMO) has become an interest of many labs in recent years. This is largely because of the multiple identified substrates for SUMOylation as well as the wide variety of effects that modification by SUMOylation can have on these substrates. A yeast two-hybrid assay using the Glis3 N-terminal conserved region as bait and a murine pancreatic β cell library identified enzymes that play an important role in the process of SUMOylation as potential Glis3 interactors. Subsequently, potential SUMOylation sites were identified within a phylogenetically conserved N-terminal region of Glis3. vi We found that Glis3 was SUMOylated by PIAS-family proteins (PIAS1 and PIASy) at two conserved lysine residues within the N-terminal region of Glis3. Additionally, it was found that posttranslational modification of Glis3 by SUMOylation regulated the transactivational activity of Glis3 in a tissue-dependent manner: down- regulating target genes in a β cell environment, and up-regulating genes in a non-β cell environment. These observed effects were due to mechanisms both dependent and independent of Glis3 SUMOylation as effects were observed after the mutation of the modified conserved lysine residues. The transactivation activity of MafA, another transcription factor that plays a major role in activating target genes in β cells has previously been shown to be modulated by SUMOylation. It has also been demonstrated previously that MafA and Glis3 work synergistically to activate target genes. We found that PIASy promoted MafA SUMOylation which disrupts synergism between MafA and Glis3 at the insulin promoter. Finally, we found that chronic exposure of β cells to hyperglycemic conditions promoted Glis3 and MafA SUMOylation which was coincident with a sharp decrease in insulin transcription. These data suggest a potential mechanism that could underlie β cell dysfunction preceding type 2 diabetes and could potentially explain one mechanism by which insulin secretion is negatively affected in individuals that are incapable of regulating their blood glucose levels. Collectively, the results of this project provided novel information regarding transcriptional control of the insulin gene that is modulated by a combination of blood glucose levels and posttranslational modification. vii Table of Contents Signature Page.....................................................................................................................ii Acknowledgements............................................................................................................iii Abstract................................................................................................................................v Table of Contents...............................................................................................................vii Chapter 1: Introduction........................................................................................................1 1A: The Pancreas.....................................................................................................1 1B: Blood Glucose Homeostasis.............................................................................4 1C: GLIS3, The Gene..............................................................................................5 1D: GLIS3, The Protein...........................................................................................5 1E: Glis3 Localization.............................................................................................6 1F: Glis3-Associated Pathologies............................................................................7 1G: Glis3-Mediated Gene Regulation.....................................................................8 1H: MafA.................................................................................................................9 1I: Posttranslational Modifications........................................................................10 1J: SUMOylation...................................................................................................12 1K: Pathologies Associated with SUMOylation....................................................14 Chapter 2: Materials and Methods.....................................................................................16 2A: Cells and Growth Conditions..........................................................................16 2B: Generation of Plasmids and Constructs..........................................................16 2C: Reporter Assays..............................................................................................18 2D: Co-Immunoprecipitation Assays....................................................................19 2E: Western Blot Analysis and Protein Quantification.........................................20 2F: Quantitative Reverse Transcriptase Real-Time PCR Analysis.......................20 2G: Immunocytochemistry and Microscopy..........................................................21 Chapter 3: Results..............................................................................................................23
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