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Characterization of Chromatin Interaction in Mammalian Cells Jufen Zhu University of Connecticut - Storrs, [email protected]

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Characterization of Chromatin Interaction in Mammalian Cells Jufen Zhu University of Connecticut - Storrs, Jacquelinejufenzhu@Gmail.Com University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 1-8-2019 Characterization of Chromatin Interaction in Mammalian Cells Jufen Zhu University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Zhu, Jufen, "Characterization of Chromatin Interaction in Mammalian Cells" (2019). Doctoral Dissertations. 2053. https://opencommons.uconn.edu/dissertations/2053 Characterization of Chromatin Interaction in Mammalian Cells Jacqueline Jufen Zhu, Ph.D. University of Connecticut, 2019 Abstract Higher-order chromatin organization in cell nucleus is mysterious. Microscopy and high- throughput sequencing technologies have been applied to reveal the connections between genome structure and gene transcription, which is the main topic of my thesis. Higher-order chromatin organization differs across cell types and species, giving an insight into disease genesis and tumorigenesis. Despite an enormous progress has been made recently in epigenomic study, lots of things remain unknown. My dissertation reviews the current understanding of epigenomics, characterizes chromatin interaction in mammalian cells using different technologies, investigates chromatin reorganization in breast cancer cells, analyzes integrated genomic and epigenomic data in breast cancer metastasis and discusses results and future directions. Dissertation Jacqueline Jufen Zhu Characterization of Chromatin Interaction in Mammalian Cells Jacqueline Jufen Zhu B.E., Nanjing Agricultural University, 2010 M.S., Chinese Academy of Sciences, 2013 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2019 i Dissertation Jacqueline Jufen Zhu Copyright by Jacqueline Jufen Zhu 2019 ii Dissertation Jacqueline Jufen Zhu Approval Page Doctoral of Philosophy Dissertation Characterization of Chromatin Interaction in Mammalian Cells Presented by Jacqueline Jufen Zhu, M.S. Major Advisor_____________________________________________________ Yijun Ruan Associate Advisor_____________________________________________________ Blanka Rogina Associate Advisor_____________________________________________________ James Li Associate Advisor_____________________________________________________ Derya Unutmaz Associate Advisor_____________________________________________________ Jeff Chuang University of Connecticut 2019 iii Dissertation Jacqueline Jufen Zhu Acknowledgements Time flies. It feels like only days ago that I came here to start my PhD study, though actually it is about time to say goodbye. Lots of memories, good or bad, happy or sad, emerge. Five years ago, I decided to pursue a PhD degree in the US to continue my exploration in biology, philosophy and the universe. I knew it would be a journey to a whole new world, but I did not know I would have met so many great people and lived an unforgettable life with them around. I am so grateful to be here to have a chance to improve my understanding of human, the world and the universe with the company of everyone I know. I would like to thank my supervisor Yijun for his help on my projects and life. Without him, I could not have learnt so many cutting-edge technologies in biological research; I could not have collaborated with scientists in different fields outside the institute; I could not have realized career life is this tough. I would like to thank my collaborators, Kent group and Dariusz group. We had a good time working together, communicating with each other and exchanging ideas. I would like to thank my committee members, Blanka, James, Derya and Jeff for their cooperation. As the committee chair, Blanka provided sufficient guidance for every step to my graduation. James gave lots of constructive suggestions. I would like to thank the department of Genetics and Genomic Sciences, Dr. Babara Kream, the graduate school and University of Connecticut. I would like to thank my two best girl friends, Xi and Ping. Xi is the first person I met and knew in the US. She is my classmate and roommate. We lived together for years, traveled to New York City for New Year, to Miami at Christmas, complained about school and life, did shopping at weekend, talked about everything about us and helped each other out. Till now, I iv Dissertation Jacqueline Jufen Zhu know she is one I can go to whenever and wherever I am. Ping is one of my co-workers in the lab. She is my mentor teaching me experiments in the lab, but more like a sister. She is thoughtful and caring. I am so lucky to have her during my PhD life. I would like to thank my parents and family. My parents always trust on me, on my choices and decisions. They are always on my side supporting and encouraging me. I would like to thank my mother-in-law, my sister-in-law and her family. I would like to thank everyone in the lab. Most of us work happily together. Even though there were conflicts and misunderstandings, but I know this is real life. Especially, I enjoy the companies of Emaly, Zhonghui and Minji. I would like to thank my friends in the first year of my PhD life. We did crazy things together and had a good time. I would like to thank so many other friends, Xin, Cathy, who listened to me and helped me relieve the stress. I would like to thank myself. I made my effort to complete the courses, to do the research and to publish papers. I am grateful I did things that I think are right. I am not regretful at all of everything I have done. Last but not the least, I would like to thank my best friend, my love, my soulmate and my hubby, Albert. At the first sight, he fell in love with me. At the second sight, I knew he is my destiny. He taught me programming and bioinformatics. He shared his experience of pursuing a PhD degree with me. He filled his life with dream, my life with love and our life with responsibility. I feel I can feel his dream. I feel I am lucky to have him. I feel I could give my everything to him. I am happy of feeling so. v Dissertation Jacqueline Jufen Zhu Table of Contents Chapter 1: Introduction ...................................................................................................................... 1 1.1 Overview ..................................................................................................................................... 2 1.2 Literature Review ....................................................................................................................... 3 The genome structure in three-dimension ................................................................................................. 3 Methods to study chromatin organization ................................................................................................ 9 Key regulators of genome structure ........................................................................................................ 12 Chromatin reorganization in diseases ..................................................................................................... 14 New insights into genome structure ......................................................................................................... 16 1.3 Hypothesis and Specific Aims .................................................................................................. 17 Project 1 Visualization of chromatin loop in human cells ...................................................................... 17 Project 2 Identification of metastasis-associated chromatin interaction and gene network .................. 18 Chapter 2: Super-resolution imaging of single chromatin loop in human lymphoblastoid cells ..................................................................................................................................................... 28 2.1 Introduction .............................................................................................................................. 29 2.2 Materials and Methods ............................................................................................................ 31 Cell culture ................................................................................................................................................ 31 Nuclei isolation .......................................................................................................................................... 31 Coverslip coating ....................................................................................................................................... 31 DNA FISH ................................................................................................................................................. 31 iPALM imaging .......................................................................................................................................... 31 Image pre-processing ................................................................................................................................. 32 Spots identification..................................................................................................................................... 32 Algorithms for connecting identified spots .................................................................................................. 33 Spline Interpolation ..................................................................................................................................
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