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Role of Histone Deacetylases in Gene Expression and RNA Splicing

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Role of Histone Deacetylases in Gene Expression and RNA Splicing Role of Histone Deacetylases in Gene Expression and RNA Splicing by Dilshad Hussain Khan A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba In partial fulfillment of the requirements of the degree of Doctor of Philosophy Department of Biochemistry and Medical Genetics University of Manitoba Winnipeg, Manitoba, Canada Copyright 2013 by Dilshad Hussain Khan Thesis Abstract Histone deacetylases (HDAC) 1 and 2 play crucial role in chromatin remodeling and gene expression regimes, as part of multiprotein corepressor complexes. Protein kinase CK2-driven phosphorylation of HDAC1 and 2 regulates their catalytic activities and is required to form the corepressor complexes. Phosphorylation-mediated differential distributions of HDAC1 and 2 complexes in regulatory and coding regions of transcribed genes catalyze the dynamic protein acetylation of histones and other proteins, thereby influence gene expression. During mitosis, highly phosphorylated HDAC1 and 2 heterodimers dissociate and displace from mitotic chromosomes. Our goal was to identify the kinase involved in mitotic phosphorylation of HDAC1 and 2. We postulated that CK2-mediated increased phosphorylation of HDAC1 and 2 leads to dissociation of the heterodimers, and, the mitotic chromosomal exclusions of HDAC1 and 2 are largely due to the displacement of HDAC-associated proteins and transcription factors, which recruit HDACs, from chromosomes during mitosis. We further explored the role of un- or monomodified HDAC1 and 2 complexes in immediate-early genes (IEGs), FOSL1 (FOS-like antigen-1) and MCL1 (Myeloid cell leukemia-1), regulation. Dynamic histone acetylation is an important regulator of these genes that are overexpressed in a number of diseases and cancers. We hypothesized that transcription dependent recruitment of HDAC1 and 2 complexes over the gene body regions plays a regulatory role in transcription and splicing regulation of these genes. We present evidence that CK2-catalyzed increased phosphorylation of HDAC1 and 2 regulates the formation of distinct corepressor complexes containing either HDAC1 or HDAC2 I homodimers during mitosis, which might target cellular factors. Furthermore, the exclusion of HDAC-recruiting proteins is the major factor for their displacement from mitotic chromosomes. We further demonstrated that un- or monophosphorylated HDAC1 and 2 are associated with gene body of FOSL1 in a transcription dependent manner. However, HDAC inhibitors prevented FOSL1 activation independently of the nucleosome response pathway, which is required for IEG induction. Interestingly, our mass spectrometry results revealed that HDAC1 and 2 interact with a number of splicing proteins, in particular, with serine/arginine-rich splicing factor 1 (SRSF1). HDAC1 and 2 are co-occupied with SRSF1 over gene body regions of FOSL1 and MCL1, regardless of underlying splicing mechanisms. Using siRNA-mediated knockdown approaches and HDAC inhibitors, we demonstrated that alternative splicing of MCL1 is regulated by RNA- directed localized changes in the histone acetylation levels at the alternative exon. The change in histone acetylation levels correlates with the increased transcription elongation and results in change in MCL1 splicing by exon skipping mechanism. Taken together, our results contribute to further understanding of how the multi-faceted HDAC1 and 2 complexes can be regulated and function in various processes, including, but not limited to, transcription regulation and alternative splicing. This can be an exciting area of future research for therapeutic interventions. II Acknowledgements I owe my deepest gratitude to all those people who have helped me through the completion of this dissertation with their endless support, contributions, and encouragement. Because of them, my graduate school life and experience has been one that I will remember and cherish forever. First of all, I am greatly indebted to my supervisor, Dr. Jim Davie. Throughout the years, his invaluable guidance, motivation, expertise and enthusiastic support have made this a thoughtful and rewarding journey. He has truly been an inspiration for me to become an independent researcher. I could not have imagined having a better advisor. I hope that I can in turn, pass on the research values and passion that he has instilled in me. My sincere thanks go to the members of my thesis advisory committee: Dr. Lorrie Kirshenbaum, Dr. Etienne Leygue, and, Dr. Kirk McManus for their guidance over the years. Their continuous support and insightful advices have driven my project further, and, helped to reach at this accomplishment. I owe them my heartfelt appreciation. I would also like to acknowledge Dr. Philippe Georgel from Marshall University, for his critical review of my thesis and for taking the time to attend my oral defence. I consider it an honor to work in Davie lab with my companions, a talented team of ‘crazy’ researchers. The former lab members Dr. Bojan Drobic, Dr. Paula Espino and Dr. Jian Min Sun were instrumental to me in learning techniques and to start up my project. Ms. Cheryl Peltier, our III ‘Lab Mom’, always had what I was looking for, whether it be a reagent, lab supply or a protocol. She has been a good friend. I appreciate her generosity for providing the delicious cakes and cookies, which helped me to survive the long hours and weekends in the lab! Very special thanks to Dr. Shihua He, Dr. Jenny Yu and Dr. Wenguang Cao, with whom I have worked in a number of projects. I specially acknowledge Dr. Shihua He for all his help, advice and for his wonderful immunofluorescence data presented in this thesis. A Big ‘Thank you’ goes to Ms. Carolina Gonzalez, who spent months to run ‘the radioactive gels’ to help me in the splicing project. I would like to greatly acknowledge Dr. Soma Mandal, my bench mate and a very good friend, for being a great person to whom I could always talk about my ideas, excitements, struggles, frustrations and problems and, for the innumerable discussions and fun times over the ‘Tea parties’. You took the pain to go through the drafts of my thesis chapters in a very short time! Thank you for being there to support and encourage me, and, for the many precious memories along the way. I have also enjoyed the company of Dr. Shannon Healy and Ms. Protiti Khan as my ‘bay mates’ for sharing all the crazy ideas, discussions, and, for the many laughs. I have got the habit to expect Shannon, a humorous and dedicated person, in the lab in the weekends and after hours. She always remembers to tell me when she is going for climbing and I have to stay in lab! My gratitude is extended to Dr. Wayne Xu, Dr. Deborah Tsuyuki, Ms. Xuemei Wang, Ms. Nehal Patel, and Ms. Donna Lee, and, to the fellow lab mates Sanzida Jahan and Alekxandar Ilic. It is been a pleasure to work with you all. I would like to give a heartfelt thanks to our collaborators Dr. Etienne Leygue and Mr. Charlton Cooper here at University of Manitoba, Dr. Stefan Winter and Dr. Christian Seiser at Medical University of Vienna, and, Dr. Karen Smith and Dr. Jerry Workman at Stowers Institute for IV Medical Research, who were involved in the respective projects from the beginning and also for all their invaluable insights, suggestions, support and help over these years. My special appreciation to all the amazing office supports of Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology and Manitoba Institute of Child Health, especially Ms. Cecile Verrier, Ms. Mary Marko, Ms. Nikki Rayan, and, Ms. Debbie Korpesho to help me out whenever I expressed a complete lack of knowledge about paper works and procedures. A deeply felt thanks to Ms. Tuntun Sarkar, who has been kind enough to advise and to help in any matters related to graduate studies, and, for all her supports throughout the years. I am very grateful to the Manitoba Institute of Cell Biology and Manitoba Institute of Child Health for providing the stimulating training environment. I would also like to acknowledge the financial supports of Manitoba Health Research Council and University of Manitoba Graduate Studentship. Last, but not the least, I would like to express my immense gratitude to my parents and to my husband, Zinnatun Nabi. My parents are the reason I have started this journey. My husband, who has been a never-ending source of love, inspiration, encouragement, support and strength all these years, is my ‘driving force’ to reach the end of this journey. I cannot thank you enough. This is a tribute to three of you. I hope that this work will make you proud. V In loving memory of my father Late Nazibul Hussain Khan VI Table of Contents Thesis abstract……………………………………………………………………..I Acknowledgements……………………………………………………………...III Dedication………………………………………………………………………..VI Table of contents………………………………………………………………..VII List of Tables…………………………………………………………………...XIV List of figures………………………………………………………………......XIV List of abbreviations………………………………………………………….XVII List of copyright materials for which permission was obtained…………..XXII Chapter 1: Introduction…………………………………………………………..1 1.1 Chromatin structures and modifications……………………………………………….......2 1.1.1 The building block of chromatin: nucleosome……………………………………………2 1.1.2 Chromatin modifications………………………………………………………….............4 1.1.3 Histone modifications…………………………………………..........................................5 1.1.3.1 Histone acetylation………………………………………………………………………...8 1.1.3.2 Histone phosphorylation…………………………………………………………………10 1.1.3.3 Histone methylation……………………………………………………….......................12
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