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Understanding the Role of Transcription Factor Regulation of Development Understanding The Role Of Transcription Factor Regulation Of Development Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Allison Marie Webb Chasser The Ohio State Biochemistry Graduate Program The Ohio State University 2019 Dissertation Committee Dr. Helen Chamberlin, Advisor Dr. Jane Jackman, Program Advisor Dr. Harold Fisk Dr. Kotaro Nakanishi Copyright by Allison Marie Webb Chasser 2019 Abstract Coordinated development is the process of directing cell growth, differentiation, and proliferation. The initiation and integration of these varied events often begins directly at the level of transcription in order to regulate which gene products are available to perform temporally and spatially restricted functions. This regulation requires transcription factors to activate genes necessary for developmental outcomes and future cell phenotypic programs. In this work, I focus on the transcription factors EGL-38/PAX and PAL-1/HOX and their involvement in cellular regulatory networks. Pax proteins represent a dynamic method of regulation, as they can act in different cell types to perform varied functions which are all necessary for the directed organization of a single system. Hox genes, in comparison, represent the more stable gene regulatory network, which acts in singular cells to perform specific functions necessary for establishing a body plan. EGL-38/PAX and PAL-1/HOX reflect these paradigms in Caenorhabditis elegans. I have investigated how EGL-38/PAX can act in neighboring, distinct cell types of the developing egg-laying system to coordinate its own expression through the Epidermal Growth Factor signaling pathway as well as activate a cellular program of genes required for egg-laying behavioral output. I have examined how PAL-1/HOX can control expression of a range of transcription factors necessary for cell differentiation, informed by the predictions of two separate computational models of the PAL-1 regulatory network. Altogether, my results inform i the larger knowledge of how Pax and Hox genes function, dynamically and statically, in transcriptional activation and gene regulatory networks during development. ii Acknowledgements I would like to thank Dr. Helen Chamberlin for her mentorship in graduate school, and to thank my committee members for their participation and their patience. I would like to thank all of my worm group people, particularly my best friends Dr. Brittany Suggs, Dr. Karley Mahalak, and Kristin Balmert, without whom I would not have made it through graduate school. I want to thank Marcos Corchado, Leanne Kelley, Dr. Ryan Johnson, Monica Scanu, Kristen Navarro, and all the undergraduates who have passed through our lab, for their support, their aid, and their laughter. Finally, I would like to show gratitude to my family for all their love and support over the years. Without them, I would not have endeavored to complete this degree and dissertation, and I sincerely thank them all for their forbearance and understanding. To my Mom and Dad, thank you for everything you’ve ever sacrificed for me and everything you’ve ever done to aid me to becoming a PhD. Your love and encouragement have always been with me. To my brother Eric and sister-in-law Maria, thank you for your love and for all your attempts to help me out figuring out my life over the years. To my daughter Ella, thank you for love and understanding when I couldn’t play with you because I needed to write. Your happy laughter has helped this process along. And to my husband Stephen, thank you for putting up with everything I’ve emotionally thrown at you while I have been in graduate school. You’ve given me so much love and understanding as I have completed this journey and I couldn’t have done it without you. Thank you to all who have been involved. iii Vita March 12, 1990…………………………........Born, Cincinnati, OH 2008…………………………………………..Graduation, Ursuline Academy 2008-2012……………………………………B.S. Biochemistry and Molecular Biology, Marquette University, with a minor in mathematics 2012-2019……………………………………Graduate Teaching and Research Associate, The Ohio State University Publications Manuscript to be published: “EGL-38/Pax coordinates development in the Caenhorhabditis elegans egg-laying system through EGF pathway dependent and independent functions” Allison Webb Chasser, Ryan Johnson, Helen Chamberlin 2019; Requested revisions submitted to Mechanisms of Development Previously published manuscript: “Visualizing Multidimensional Data with Glyph SPLOMs: Visualizing Multidimensional Data with Glyph SPLOMs” Andrew Yates, Allison Webb (Chasser), Michael Sharpnack, Helen Chamberlin, Ken Huang, Raghu Machiraju Published in: Computer Graphics Forum, 2014, 33:3, 301-310 DOI 10.1111/cgf.12386 ; ISSN 01677055 Fields of Study Major Field: The Ohio State Biochemistry Program Focus: Molecular Genetics and Development iv Table of Contents Abstract ........................................................................................................................ i Acknowledgements ...................................................................................................... iii Vita ..............................................................................................................................iv List of Figures ..............................................................................................................ix Appendix: Tables ......................................................................................................... x Chapter 1 Introduction ..................................................................................................... 1 1.1 Transcription factors in cell differentiation and specification .................................. 1 1.1.1 Pax proteins ........................................................................................................ 2 1.1.1.1 Pax proteins in development............................................................................ 3 1.1.1.2 Pax proteins in cancer ..................................................................................... 5 1.1.1.2.1 Example of Pax protein activity in cancer ..................................................... 7 1.1.2 Hox proteins........................................................................................................ 8 1.1.2.2 Hox proteins in cancer ................................................................................... 10 1.1.3 Transcription factors as cancer targets ............................................................. 11 1.2 Inductive cell-to-cell signaling .............................................................................. 13 1.2.1 Epidermal Growth Factor Pathway ................................................................... 14 1.2.2 EGF signaling in cancer .................................................................................... 14 1.3 Computational methods to model regulatory networks ........................................ 15 1.4 Research question and chapter preview .............................................................. 16 1.5 Figures ................................................................................................................. 19 Chapter 2: EGL-38/Pax coordinates development in the Caenhorhabditis elegans egg- laying system through EGF pathway dependent and independent functions ................ 23 2.1 Introduction .......................................................................................................... 24 2.2 Materials and Methods ........................................................................................ 28 2.2.1 Genetic strains and worm culture ..................................................................... 28 2.2.2 Generating tagged EGL-38:GFP ...................................................................... 28 2.2.3 Generating nlp-2 and nlp-7 reporters and deletion transgenes ......................... 30 2.2.4 Microscopy........................................................................................................ 31 2.2.5 U0126 experiments ........................................................................................... 31 v 2.2.6 Protein Expression and EMSA .......................................................................... 32 2.3 Results ................................................................................................................. 33 2.3.1 EGL-38 protein is expressed during the development of the C. elegans egg- laying system ............................................................................................................. 33 2.3.2 EGL-38 expression in uv1 is dependent on EGF signaling ............................... 34 2.3.3 Expression of neuropeptide genes nlp-2 and nlp-7 in the uv1 cells is dependent on EGF signaling and egl-38 ..................................................................................... 36 2.3.4 EGFR activation bypasses the requirement for egl-38 to promote uv1 cell placement, but not neuropeptide gene expression. ................................................... 38 2.3.5 nlp-2 is a direct target for EGL-38 in uv1 cells .................................................. 39 2.4 Discussion ........................................................................................................... 41 2.5 Figures ................................................................................................................
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