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Novel Mechanisms of Transcriptional Repression by the Paired- Like Homeodomain Transcription Factor Goosecoid

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Novel Mechanisms of Transcriptional Repression by the Paired- Like Homeodomain Transcription Factor Goosecoid Novel mechanisms of transcriptional repression by the paired- like homeodomain transcription factor Goosecoid. by Luisa Izzi A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Medical Biophysics University of Toronto © Copyright by Luisa Izzi (2008) Novel mechanisms of transcriptional repression by the paired-like homeodomain transcription factor Goosecoid Doctor of Philosophy, 2008 Luisa Izzi Department of Medical Biophysics, University of Toronto Abstract Gastrulation is the process by which the three germ layers are generated during vertebrate development. Nodal ligands, which form a subgroup of the Transforming Growth Factor β (TGFβ) superfamily, regulate the expression several transcription factors implicated in gastrulation. Among these are the paired-like homeodomain transcription factors Goosecoid (Gsc) and Mixl1. At the molecular level, Gsc has been described to function as a transcriptional repressor by directly binding to paired homedomain binding sites on target promoters. Here, I describe a novel mechanism of transcriptional repression by Gsc. Using a molecular and embryological approach, I demonstrate that the forkhead transcription factor Foxh1, a major transducer of Nodal signaling, associates with Gsc which in turn recruits histone deacetylases to negatively regulate Mixl1 expression during early mouse development. Post-translational modification of transcription factors by SUMO proteins represents an important mechanism through which their activity is controlled. Here, I also demonstrate that Gsc is sumoylated in mammalian cells by members of the PIAS family of proteins and this modification potentiates the repressive activity of Gsc on direct targets such as the Xbra and Gsc promoters, but not on indirect targets such as Mixl1. Taken together, work presented in this thesis describes two novel mechanisms of transcriptional repression by Gsc. ii Dedication I would like to dedicate this thesis to my beloved and late grandmother Onorina Fedele (July 27 1923-February 10, 1999), a woman who faced life’s hardships with strength, courage and grace. She will forever be a source of inspiration! “Nella vita, si deve essere sempre guerriere!” Elisabetta Fedele (Nettuno, Italy, February 25, 2008) iii Acknowledgments Completing a PhD thesis is a Herculean task that can be exasperating at times. However, the exhilaration that is felt when a scientific discovery is made compensates for all the sacrifices that are made along the way. During the last eight years, so many people have contributed on many different levels to help me achieve this goal. I would first like to thank my supervisor Dr. Liliana Attisano for welcoming me in her lab and giving me the opportunity to pursue my degree under her guidance. Lil, thank you for all you have done over the years to help me find it within myself to achieve my goals. I would also like to thank Dr. Jeff Wrana, a close scientific collaborator and a member of my graduate supervisory committee, for all his contributions. Jeff, I greatly appreciate the time and ressources you dedicated to my PhD research project over the years. As well, I would like to extend my gratitude to Drs. Jane McGlade and Corinne Lobe, who as members of my graduate committee members have followed my progress and provided insight into my doctoral research. As a member of the Attisano lab, I had the opportunity to work with a select group of very talented young scientists. Over the years, so many of you have become very close friends. I am very appreciative for the kindness and friendship you have shown me over the years. I am especially thankful to Cristoforo Silvestri and Etienne Labbé. I began this journey with you so many years ago, and I have learned so much from you (both scientific and non-scientific). A very special thank you to Garnet Lau for the compassion you showed me when I was working long hours to complete the revisions for my paper. I was so lucky to have you as a little sister in the lab, always making sure that I had something to eat for dinner and a little snack for my walk home. Thank you to Stephen Perusini and Roberta De Oliviera for their camaraderie. I would also like to extend my gratitude to members of the Wrana lab, especially to Masahiro Narimatsu and Abi Ogunjimi. Over the years, you have all been so generous with your time and your expertise. I made so many friends while I was in Toronto, and all had such a great impact on my life. I am so thankful to Andrea, Arun, Hassina, Miriam, Tuba, and Francoise for being such great friends over the years. A special thank you to Lesley MacNeil, my thesis writing buddy, for listening to my complaints while we were writing our dissertations at the library. Also, I would like to thank Christine for being my big sister in Toronto, for your sound advice and your continued support. To all my friends and family back in Montreal, thank you for keeping in touch and encouraging me along the way. To my surrogate family in Toronto, the Santillis, I will never forget the kindness and generosity you have shown me over the years. Finally, I am grateful to my parents Elena and Beniamino and my brother Lorenzo, without your love and support none of this would have been possible. Mom and Dad, I’ll never forget all the sacrifices you have made to allow me to pursue my dreams. I hope I can always make you proud! iv Table of Contents Dedication................................................................................................................................................................... iii Acknowledgments.......................................................................................................................................................iv Table of Contents.........................................................................................................................................................v List of Tables............................................................................................................................................................ viii List of Figures .............................................................................................................................................................ix List of Abbreviations...................................................................................................................................................x CHAPTER 1 Introduction .................................................................................................................................................................1 1.1 Overview of early development in model systems ......................................................................................2 1.1.1 Early amphibian development ...............................................................................................................3 1.1.2 Early fish development..........................................................................................................................6 1.1.3 Early mammalian development ...........................................................................................................10 1.2 Nodal signaling during early development...............................................................................................14 1.2.1 Ligands ................................................................................................................................................14 1.2.2 Receptors and Co-receptors.................................................................................................................15 1.2.3 Signal transducers: Smads ...................................................................................................................20 1.2.3.1 Smad Activation.........................................................................................................................20 1.2.3.2 Role of Smads in early mouse development ..............................................................................22 1.2.4 Smad DNA binding partners ...............................................................................................................24 1.2.4.1 Foxh1 .........................................................................................................................................25 1.2.4.1.1 Foxh1 structure-function .......................................................................................................25 1.2.4.1.2 Foxh1 expression in early development ................................................................................26 1.2.4.1.3 Foxh1 function during early development.............................................................................28 1.2.4.1.4 Foxh1 target genes.................................................................................................................30 1.2.4.1.5 Modulation of Foxh1-dependent transcription ......................................................................32 1.2.4.2 Mixer and p53 ............................................................................................................................33 1.2.5 Smad transcriptional cofactors.............................................................................................................34 1.2.5.1 Transcriptional coactivators .......................................................................................................34 1.2.5.2 Transcriptional co-repressors .....................................................................................................35
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