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Zinc Finger Protein Zfp335 Is Required for the Formation of the Naïve T Cell Compartment.” the Co-Authors on This Publication Were Shuang

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Zinc Finger Protein Zfp335 Is Required for the Formation of the Naïve T Cell Compartment.” the Co-Authors on This Publication Were Shuang Copyright (2015) by Brenda Yuyuan Han ! ii! ACKNOWLEDGEMENTS My time in graduate school has been a transformative period in my life, during which I have learned and grown tremendously both as a scientist and as a person, and I would like to take this opportunity to express my heartfelt gratitude to those who have helped me along the way. First and foremost, I would like to thank my Ph.D supervisor Dr. Jason Cyster for his exceptional guidance and mentorship throughout the five years I have spent in his lab. I would be the first to admit that I started graduate school with only the haziest comprehension of how the scientific process really worked, but Jason has since taught me many invaluable lessons in being a good scientist, such as how to engage with the literature, design informative experiments, analyze and interpret data with care and rigor. From Jason, I learned the value of performing experiments iteratively, allocating time and resources efficiently, and maintaining focus and discipline in my efforts to keep moving my project forward. He has been patient, encouraging and supportive as a mentor, and for that I will always be grateful. I would also like to thank Mark Ansel and Art Weiss, who have been so generous with their time as members of my qualifying exam committee and thesis committee. I have benefitted greatly from their insightful and constructive feedback on my thesis work both during and outside of committee meetings, and I will continue to seek their counsel on career and life beyond graduate school. Various Cyster lab members, both past and present, have been an integral part of my graduate school experience and I feel fortunate to have had the opportunity to work alongside so many talented and energetic individuals. I am grateful to Lisa Kelly and Betsy Gray for sharing their senior grad student wisdom and for their kind words of encouragement back when I was still a clueless novice. In particular, I owe a huge debt of gratitude to Betsy: no matter how busy ! iii! she was, she somehow always managed to find time to help and give me advice when I needed it. Betsy’s compassionate and generous spirit, disciplined work habits, organizational skills and conscientiousness were qualities that I greatly admired, and to this day I still think of her as my role model in lab. Tim Schmidt’s irrepressible good nature, upbeat attitude and overall bold approach to science and life made him an awesome lab sibling, and I shall always cherish the memory of how we worked together to organize a wildly successful Immunology Happy Hour that decisively raised the bar for all subsequent events. I can always rely on fellow graduate students Lauren Rodda and Eric Dang for enjoyable, refreshingly uncynical conversations, and I like to think that between the three of us we have for ourselves a Cyster lab grad student support circle. Lauren has an inquiring mind and a penchant for asking questions that force me to rethink my assumptions. Eric combines a towering scientific intellect with a wicked sense of humor and a cheerful willingness to help, and I very much appreciate having him as a bay mate, co- conspirator and (occasional) singing partner. One of the best things about being in the Cyster lab is that with so many talented postdocs around, there was always someone I could go to if I needed guidance. Kazuhiro Suzuki, my rotation mentor, was a patient teacher and careful scientist who showed me the gold standard in lab technique. Oliver Bannard added a distinctly British flavor to the lab humor dynamics; he possesses a scientific acuity and passion for grappling with complexity that I truly appreciate and admire. I have the greatest respect for Tangsheng Yi, who not only was an awe-inspiring juggernaut of productivity but also an eternally cheerful dispenser of practical wisdom about work and life. Andrea Reboldi, my benchmate of five years who joined the lab at around the same time as I did, knows everything about everything and is a prolific purveyor of quality scientific advice and gossip. Francisco “Paco” Ramírez-Valle, our resident dermatologist, joined ! iv! our bay a couple years later and has been a model of medical professionalism as well as a continuing boon to lab morale ever since. Jagan Muppidi is our go-to guy for everything from Plat-E cells to iOS upgrades and these days he seems to be the lab’s token grown-up. Michael Barnes is an integral (if idiosyncratic) part of the lab’s social fabric and has been a steady source of project-specific feedback and bubble wrap-popping noises over the years. I would like to give special thanks to my co-author Shuang Wu: her biochemistry expertise and hard work were indispensable to the work presented in this thesis, and she has been a dependable teammate throughout the course of this project. Many thanks also to Robert Horton, with whom I worked closely on bioinformatics analysis. His enthusiasm and programming skills were instrumental to moving the project forward, and he was always happy to instruct me on the intricacies of R and Unix. I also owe many thanks to the people who keep the wheels of the lab turning (more-or- less) smoothly. Claire Chan, our amazing administrative assistant, takes care of everything from ordering reagents to arranging for equipment repair to printing FedEx shipping labels; were it not for her effectiveness at getting things done, I am certain that the lab would fall apart within days. Ying Xu, our molecular biology specialist, taught me how to clone my first construct and perform my first real-time PCR analysis, and I feel fortunate to be able to tap on her vast store of experience. Jinping An’s help in the mouse room has allowed me to keep both my mouse colony as well as my time spent in the bowels of LARC under control. I am also thankful for our wonderful lab assistant Bernarda Lopez, who performs most of the mundane, time-consuming lab chores so the rest of us can focus on research and never have to worry about running out of clean glassware or buffers. ! v! I would like to express my sincere thanks to Lisa Magargal, Monique Piazza, Nathan Jew, Demian Sainz and the rest of the Biomedical Sciences office staff for their excellent administrative support throughout the course of graduate school. I also wish to thank my family, whose unconditional love has endured throughout all the long years I have spent away from home and on distant shores. Lastly, mere words alone cannot convey my gratitude for Chuan- Sheng Foo, who has not only been a bedrock of emotional support and constant encouragement, but also is the best scientific collaborator one could hope for. Many of my best ideas were developed during our weekend discussion sessions and without him, this dissertation would literally have not been possible. Thank you for everything, CS. ! vi! CONTRIBUTIONS TO PRESENTED WORK All work in this dissertation was done under the direct supervision and guidance of Dr. Jason G. Cyster. Chapter 2 was published in eLife as “Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment.” The co-authors on this publication were Shuang Wu, Chuan-Sheng Foo, Robert M. Horton, Craig N. Jenne, Susan R. Watson, Belinda Whittle, Chris C. Goodnow and Jason G. Cyster. Dr. Jason Cyster and I collaboratively conceptualized and designed the research presented in this paper. The original ENU mutagenesis screen was designed and carried out by C.N. Jenne and S.R. Watson at the Australian National University under the supervision of J.G. Cyster and C.C. Goodnow. C.N. Jenne performed genetic mapping and B. Whittle coordinated exome sequencing which identified the Zfp335bloto mutation. S. Wu and I collaboratively designed the EMSA experiments in Fig. 7; all EMSA experiments in this paper were performed by S. Wu. Ying Xu designed allele-specific PCR primers for genotyping of Zfp335bloto mutant mice, cloned Zfp335 retroviral constructs, and prepared cDNA from cells I had sorted for quantitative RT-PCR analysis and Affymetrix array hybridization. R.M. Horton provided bioinformatics support for earlier analyses of ChIP-seq data leading up to the final version presented in this manuscript, which I developed in collaboration with C-S. Foo. C-S. Foo performed the motif analyses in Fig. 7C and 7D and also provided helpful discussion regarding the manuscript. I performed all other experiments, interpreted the data and generated the figures. I wrote and revised the manuscript in consultation with Dr. Jason Cyster. ! vii! Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment Brenda Yuyuan Han ABSTRACT The generation of naïve T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. Through ENU mutagenesis screening, we identified a mouse mutant, bloto, characterized by a deficiency in naïve T cells. The causative genetic lesion was identified as a hypomorphic mutation in the zinc finger protein Zfp335. Zfp335bloto/bloto mice had a paucity of naïve T lymphocytes due to a cell- intrinsic defect in mature thymocytes, as well as in peripheral T cells that have recently undergone thymic egress. The T cell defect in Zfp335bloto/bloto mice could not be explained by altered thymic selection, proliferation or Bcl2-dependent survival. ChIP-seq analysis revealed that Zfp335 binds primarily to promoter regions, and we identified a set of target genes in thymocytes that are enriched in categories related to protein metabolism, mitochondrial function, and transcriptional regulation.
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