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Characterizing the Relationship Between Williams Syndrome Transcription Factor and Heterochromatin Maintenance Through the Targe

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Characterizing the Relationship Between Williams Syndrome Transcription Factor and Heterochromatin Maintenance Through the Targe Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2013 Characterizing the Relationship Between Williams Syndrome Transcription Factor and Heterochromatin Maintenance Through the Targeted Disruption of the BAZ1B Gene Ashley E. Culver-Cochran Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES CHARACTERIZING THE RELATIONSHIP BETWEEN WILLIAMS SYNDROME TRANSCRIPTION FACTOR AND HETEROCHROMATIN MAINTENANCE THROUGH THE TARGETED DISRUPTION OF THE BAZ1B GENE By ASHLEY E. CULVER-COCHRAN A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Summer Semester, 2013 Ashley E. Culver-Cochran defended this dissertation on June 28, 2013. The members of the supervisory committee are: Brian P. Chadwick Professor Directing Dissertation Myra M. Hurt University Representative Jonathan H. Dennis Committee Member Karen M. McGinnis Committee Member Hengli Tang Committee Member The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements. ii To my husband Joshua And my loving family iii ACKNOWLEDGEMENTS I would like to express my sincerest gratitude to Dr. Brian P. Chadwick for the mentoring he has provided me throughout my time at Florida State. I am especially grateful for all the time he has spent helping me to develop my researching abilities. I feel lucky to have had the opportunity to work alongside such a great advisor. I would also like to express my appreciation to the members of my committee, including Dr. Myra M. Hurt, Dr. Jonathan H. Dennis, Dr. David M. Gilbert, Dr. Karen M. McGinnis, and Dr. Hengli Tang, for their support, guidance, and constant willingness to assist me throughout the course of my studies. Several individuals have provided invaluable support over the course of this process. Specifically, I would like to extend my gratitude to Ruth Didier for assistance with FACS sorting and live cell imaging, and Steve Miller for assistance with the microarray hybridization. I would also like to thank the members of the Chadwick lab, both past and present, including Nicole Baita, Sunny Das, Emily Darrow, Debbie Figueroa, Gregg Hoffman, Andrea Horacova, April Keating, Christine McLaughlin, Shawn Moseley, Andrew Seberg, Deanna Tremblay, and Elizabeth Walker for their advice and their encouragement. Not least, I would also like to thank my family for their unconditional love and support and I am especially appreciative of and indebted to my husband Joshua for his constant encouragement as we navigated this adventure together. iv TABLE OF CONTENTS List of Tables ................................................................................................................................ vii! List of Figures.............................................................................................................................. viii! Abstract............................................................................................................................................x! CHAPTER 1: INTRODUCTION....................................................................................................1! 1.1 Background........................................................................................................................1! 1.1.1 Williams-Beuren syndrome (WBS)............................................................................1! 1.1.2 Williams syndrome transcription factor (WSTF) and WBS.......................................1! 1.1.3 Function of WSTF ......................................................................................................3! 1.1.4 WSTF-containing chromatin-remodeling complexes.................................................4! 1.2 Goals and implications.......................................................................................................5! 1.3 Structure of the dissertation ...............................................................................................6! CHAPTER 2: DEFINING THE RELATIONSHIP OF WSTF WITH THE HUMAN INACTIVE X CHROMOSOME.........................................................................................................................7! 2.1 Introduction........................................................................................................................7! 2.2 Materials and Methods.....................................................................................................10! 2.2.1 Cell culture and BrdU labeling .................................................................................10! 2.2.2 Antibodies.................................................................................................................10! 2.2.3 Immunofluorescence (IF), immuno-DNA FISH, and immuno-RNA FISH.............11! 2.2.4 Fluorescence in situ hybridization probe preparation...............................................12! 2.2.5 Image acquisition......................................................................................................12! 2.3 Results..............................................................................................................................12! 2.3.1 Transient association of WSTF with the human Xi..................................................12! 2.3.2 The WICH complex localizes to the Xi....................................................................13! 2.3.3 WICH interacts with the Xi during its replication in late S phase............................16! 2.3.4 WICH associates with the Xi before BRCA1 and !-H2A.X ....................................18! 2.3.5 WICH shows minimal overlap with some but not all chromatin features of the Xi.22! 2.4 Discussion........................................................................................................................30! CHAPTER 3: LOSS OF WSTF RESULTS IN SPONTANEOUS FLUCTUATIONS OF HETEROCHROMATIN FORMATION AND RESOLUTION, COMBINED WITH SUBSTANTIAL CHANGES TO GENE EXPRESSION .............................................................33! 3.1 Introduction......................................................................................................................33! 3.2 Materials and Methods.....................................................................................................35! 3.2.1 Cell culture................................................................................................................35! 3.2.2 Generating BAZ1B knockout cell lines.....................................................................35! 3.2.3 WSTF rescue.............................................................................................................36! 3.2.4 Antibodies.................................................................................................................36! 3.2.5 DNA and RNA FISH probes ....................................................................................37! 3.2.6 Western blotting........................................................................................................37! 3.2.7 DNA and RNA FISH and indirect immunofluorescence .........................................38! 3.2.8 Image acquisition......................................................................................................39! 3.2.9 HP1-GFP Expression constructs...............................................................................39! v 3.2.10 Fluorescence activated cell sorting (FACS) analysis..............................................39! 3.2.11 Microarray gene expression analysis......................................................................39! 3.2.12 Quantitative RT-PCR Analysis...............................................................................40! 3.2.13 Standard RT-PCR Analysis ....................................................................................40! 3.3 Results..............................................................................................................................42! 3.3.1 Disruption of the BAZ1B gene using zinc finger nuclease technology.....................42! 3.3.2 Loss of WSTF does not impact chromatin of the human Xi ....................................45! 3.3.3 Cells lacking WSTF exhibit unique cellular and nuclear phenotypes ......................48! 3.3.4 DAPI-dense regions are enriched for constitutive heterochromatin markers...........49! 3.3.5 DAPI-dense blocks do not correspond to common nuclear structures.....................50! 3.3.6 DAPI-dense blocks in BAZ1B knockout cells are not linked to and do not disrupt the cell cycle ......................................................................................................................54! 3.3.7 Cells containing DAPI-dense blocks do not accumulate over time in culture and are not stably inherited.............................................................................................................55! 3.3.8 DAPI-dense blocks are dynamic...............................................................................56! 3.3.9 Introduction of exogenous full length WSTF ORF is sufficient to remove the appearance of DAPI-dense blocks.....................................................................................57! 3.3.10 Loss of WSTF
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