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Exploring the Role of Tet1 in Genomic Imprinting University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Exploring The Role Of Tet1 In Genomic Imprinting Jennifer Myers Sanmiguel University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biology Commons, Developmental Biology Commons, and the Molecular Biology Commons Recommended Citation Sanmiguel, Jennifer Myers, "Exploring The Role Of Tet1 In Genomic Imprinting" (2018). Publicly Accessible Penn Dissertations. 2909. https://repository.upenn.edu/edissertations/2909 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2909 For more information, please contact [email protected]. Exploring The Role Of Tet1 In Genomic Imprinting Abstract DNA methylation is an essential epigenetic mark crucial for normal mammalian development. This modification controls the expression of a unique class of genes, designated as imprinted, which are expressed monoallelically and in a parent-of-origin-specific manner. Proper parental allele-specific DNA methylation at imprinting control regions (ICRs) is necessary for appropriate imprinting. Processes that deregulate DNA methylation of imprinted loci cause disease in humans. DNA methylation patterns dramatically change during mammalian development: first, the majority of the genome, with the exception of ICRs, is demethylated after fertilization, and subsequently undergoes genome-wide de novo DNA methylation. Secondly, after primordial germ cells are specified in the embryo, another wave of demethylation occurs, with ICR demethylation occurring late in the process. Lastly, ICRs reacquire DNA methylation imprints in developing germ cells. Although much is known about DNA methylation establishment, DNA demethylation is less well understood. Recently, the Ten-Eleven Translocation proteins (TET1-3) have been shown to initiate DNA demethylation, with Tet1-/- mice exhibiting aberrant levels of imprinted gene expression and ICR methylation. Nevertheless, TET1’s role in demethylating ICRs in the female germline and controlling allele-specific expression remains to be determined. Here, we examined ICR-specific DNA methylation in Tet1-/- germ cells and ascertained whether abnormal ICR methylation impacted imprinted gene expression in F1 hybrid somatic tissues derived from Tet1-/- eggs or sperm. We show that Tet1 deficiency is associated with hypermethylation of a subset of ICRs in germ cells. Moreover, ICRs with defective germline reprogramming exhibit aberrant DNA methylation and biallelic expression of linked imprinted genes in somatic tissues. Thus, we define a discrete set of genomic regions that require TET1 for germline reprogramming and discuss mechanisms for stochastic imprinting defects. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Marisa S. Bartolomei Keywords Allele-Specific Expression, Epigenetics, Genomic Imprinting, Mouse, Primordial Germ Cell, Tet1 Subject Categories Biology | Developmental Biology | Molecular Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2909 EXPLORING THE ROLE OF TET1 IN GENOMIC IMPRINTING Jennifer Myers SanMiguel A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2018 Supervisor of Dissertation ______________________________ Marisa S. Bartolomei, Ph.D., Professor of Cell and Developmental Biology Graduate Group Chairperson ______________________________ Daniel S. Kessler, Ph.D., Associate Professor of Cell and Developmental Biology Dissertation Committee Rahul Kohli, M.D., Ph.D., Assistant Professor of Medicine and Biochemistry & Biophysics Klaus Kaestner, Ph.D., M.S., Thomas and Evelyn Suor Butterworth Professor in Genetics Jennifer E. Phillips-Cremins, Ph.D., Assistant Professor of Bioengineering Zhaolan Zhou, Ph.D., Associate Professor of Genetics EXPLORING THE ROLE OF TET1 IN GENOMIC IMPRINTING COPYRIGHT 2018 Jennifer Myers SanMiguel This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ In loving memory of my grandfather, Alan Erickson. Thank you for nurturing my love of science and delighting in my discoveries, no matter how small. iii Acknowledgements First and foremost, I want to thank my advisor, Dr. Marisa Bartolomei. I am so grateful for her tireless mentorship: reading thousands of drafts and late-night emails, sitting through countless practice talks, pushing me to the finish line, and reminding me of the big picture when I could only see details and missing pieces. Her love of science and advocacy for women in this field are attributes I will strive to emulate in my own career. Secondly, I want to deeply thank my thesis committee: Dr. Rahul Kohli, Dr. Klaus Kaestner, Dr. Jennifer Phillips-Cremins, and Dr. Zhaolan Zhou. I consider myself very lucky to have chosen such bright, thoughtful, and supportive people to work with me through my time at Penn. They have all been so happy to help when I needed it and I thank them for their mentorship and guidance. I also want to thank Dr. Rahul Kohli and Emily Schutsky for allowing us to work together to adapt their method of 5hmC profiling to pyrosequencing and thus giving me the opportunity to learn and use the technique as well. It has been a pleasure working with you both. I want to show my gratitude to my funding sources, the Genetics T32 and the NIH F31. Relatedly, I want to particularly acknowledge Dr. Meera Sundaram and Dr. Doug Epstein for their mentorship through the Genetics T32 as well as through GGR and their teaching in CAMB 550 and CAMB 608, respectively. Lastly, I want to thank Meagan Schofer for all her assistance administratively during my tenure in this program. I would like to acknowledge the wonderful training and support in all things during my Ph.D. from Dr. Joanne Thorvaldsen and Chris Krapp. Joanne was always willing to help teach or work alongside with me starting from day one in the Bartolomei lab. Her depth of knowledge, her thoughtful questions in lab meeting or on manuscript iv edits, and curiosity about my work always made me feel supported and challenged, in the best way possible. Chris similarly never hesitated to offer and assist with mouse work, ordering reagents, or helping in any way, science or otherwise. His sarcasm and humor were invaluable in keeping the lab lighthearted and fun. I sincerely appreciate everything these two individuals have given me over the past six years. My former labmates were particularly influential to my success as a student in the Bartolomei lab. I particularly want to acknowledge Dr. Lara Abramowitz for initiating the Tet1 project and continuing to support me and the project even after she started her postdoc. Dr. Rob Plasschaert is one of the smartest and most hilarious people I have ever met. I’m so happy we were baymates. I learned very valuable advice from Rob about not taking everything so seriously and learned so much from watching him think critically about science from every angle possible. Thank you both for being wonderful humans and great examples of graduate students. Dr. Martha Susiarjo was another lighthearted and warm member of the Bartolomei lab who taught me how to collect mouse oocytes. I deeply appreciate how welcome she made me when I first came to lab and the friendship and mentorship she provided while we overlapped. Lastly, I want to thank Dr. Jennifer Kalish and Dr. Sébastien Vigneau for their help and support. Jenn was also particularly helpful in sharing her new lab space for bisulfite experiments, which was instrumental in making forward progress on the Tet1 story. I shudder to think what my lab life would be like without my current labmates. Drs. Lisa Vrooman and Laren Riesche are people I could always turn to for encouragement, commiseration, a laugh, or a run to Starbucks to refuel. Thank you both for always being there to listen. My fellow graduate students, Aimee Juan and Suhee Chang are amazing, smart, talented individuals who have given me more than I can possibly put into words. Laughs, tears, drinks, and love are the four best words to v describe my relationship with these wonderful people. I was lucky enough to have Blake Alexander Caldwell first, as my rotation student, and then my friend. I truly value our conversations, whether they be about TETs, Flight of the Concords, Harry Potter houses, or the Turing test. I have learned so much from him and hope I have given back even a fraction of what he has given me. Frances Xin is a brilliant scientist, rigorous, hard- working and deeply thoughtful. In addition, she is compassionate friend and one of the best people I could have possibly been able to be side by side with during my entire Ph.D. Words cannot describe how much her love, sharp thinking, and humor have carried me through my time at Penn. I am additionally grateful to my amazing support network outside of lab. Dr. Suzi Shapira and I have been friends since we interviewed together at Penn. She is one of the most incredible people. Her intellect, resilience, and love are things I cherish and I will never stop admiring her. Dr. Katie Wetzel, Chris Wetzel, Dr. Jeffrey Rosa, Steve Goldstein, and Jackie Solomont have been constant sources of love and fun. I truly appreciate how well they took care of me, especially after my husband moved for his job and I am forever grateful for their friendship. I was additionally extremely lucky to share my entire graduate school journey with my husband, Dr. Adam SanMiguel. Being able to discuss both my frustrations and my triumphs, in painstaking scientific detail, and at long length no less, has been a gift. He never stopped believing in me and this gave me the confidence and strength to move forward when I did not think it was possible. Last but certainly not least, I also want to sincerely thank my parents, brother, extended family, and in-laws for always been so supportive and loving.
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