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Epigenetics of the Estrogen Receptors in Women Healthy Aging

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Epigenetics of the Estrogen Receptors in Women Healthy Aging Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 Epigenetic of the Estrogen Receptors in Women Healthy Aging Gardini, Elena Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-191763 Dissertation Originally published at: Gardini, Elena. Epigenetic of the Estrogen Receptors in Women Healthy Aging. 2020, University of Zurich, Faculty of Arts. Epigenetics of the Estrogen Receptors in Women Healthy Aging Thesis (cumulative thesis) presented to the Faculty of Arts and Social Sciences of the University of Zurich for the degree of Doctor of Philosophy by Elena Silvia Gardini Accepted in the fall semester 2020 on the recommendation of the doctoral committee composed of Prof. Dr. Ulrike Ehlert (main supervisor) Prof. Dr. Marta Manser Zurich, 2020 Table of Contents Acknowledgements .......................................................................................................... 6 Summary .......................................................................................................................... 7 Zusammenfassung ............................................................................................................ 8 Abbreviations ................................................................................................................. 10 1. General Introduction .................................................................................................. 11 1.1 Women healthy aging ..................................................................................................... 11 1.2 Sex steroid: definition, production and functions .......................................................... 12 1.2.1 Estrogen ................................................................................................................... 12 1.2.2 Estradiol and women health .................................................................................... 12 1.3 The estrogen receptors .................................................................................................. 13 1.3.1 Genomic signaling pathway ..................................................................................... 14 1.3.2 Non-genomic signaling pathway .............................................................................. 15 1.3.3 Distribution in the body of ERs ................................................................................ 16 1.4 Estrogen receptors and women healthy aging ............................................................... 16 1.4.1 Estrogen receptor alpha ........................................................................................... 16 1.4.2 Estrogen receptor beta ............................................................................................ 17 1.4.3 GPER ......................................................................................................................... 18 1.5 Epigenetic regulation of estrogen receptor ................................................................... 18 1.5.1 Epigenetics and human health ................................................................................. 18 1.5.2 DNA methylation ...................................................................................................... 19 1.5.3 DNA methylation during aging: “epigenetic clock” and “epigenetic drift” ............. 21 1.5.4 Estrogen receptor genes: ESR1, ESR2, GPER ............................................................ 22 1.6 Estrogen receptor genes methylation and women health ............................................ 24 1.7 DNA methylation analysis ............................................................................................... 25 1.7.1 Sources of DNA ......................................................................................................... 25 1.7.2 Tissue-specific methylation ...................................................................................... 26 1.7.3 Next-Generation Sequencing: library preparation and sequencing ........................ 26 1.8 Genetic polymorphisms of the ER genes and women health ........................................ 28 1.9 Summary ......................................................................................................................... 30 2. Conclusion, Aim of the study, and Research questions ................................................ 31 3. Results........................................................................................................................ 33 3.1 Study I: Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study .......................................................................... 33 3.1.1 Introduction.............................................................................................................. 34 3.1.2 Materials and Methods ............................................................................................ 36 3.1.3 Results ...................................................................................................................... 39 3.1.4 Discussion ................................................................................................................. 42 3.1.5 Acknowledgments .................................................................................................... 44 3.1.6 Supplementary Information ..................................................................................... 45 3.2 Study II: Sleep and Methylation of Estrogen Receptor Genes, ESR1 and GPER, in Healthy Middle-Aged and Older Women: Findings from the Women 40+ Healthy Aging Study ..................................................................................................................................... 46 3.2.1 Introduction.............................................................................................................. 47 3.2.2 Materials and Methods ............................................................................................ 48 3.2.3 Results ...................................................................................................................... 54 3.2.4 Discussion ................................................................................................................. 59 3.2.5 Acknowledgments .................................................................................................... 61 4. General Discussion...................................................................................................... 62 4.1 Summary of the findings ................................................................................................ 62 4.2 Conclusion and direction for future research ................................................................ 63 References ..................................................................................................................... 65 Appendix ........................................................................................................................ 86 Acknowledgements First and foremost, I would like to express my deep gratitude to my supervisor Professor Ulrike Ehlert for offering me the opportunity to do my PhD thesis at her Department. I also sincerely thank Prof. Ehlert for her insightful advice, constructive criticisms, and continuous support in conducting this research project. Secondly, I would like to thank the University Research Priority Program (URPP) for the intellectual and financial support which made possible the successful completion of this thesis. I would also like to acknowledge Professor Marta Manser for her willingness to be a member of my PhD committee and offering her scientific opinion in the evaluation of this thesis. My sincere thanks go to the members of the Women 40+ healthy aging study, Dr. Laura Mernone, and Dr. Serena Fiacco, for the fruitful collaboration and stimulating conversations. I would like to extend my gratitude to my fellow colleagues at the Department, Dr. Susanne Fischer, Dr. Firouzeh Farahmand, Dr. Roberto La Marca, Dr. Pearl La Marca Ghaemmaghami, for their guidance and emotional support. I thank in particular Dr. Susanne Fischer who supported me with her kindness, optimistic attitude, and insightful advice, during the years we worked together at the Department. A special mention goes to Dr. Firouzeh Farahmand for the nice working atmosphere, funny moments, and countless coffees in time of desperate needed breaks. For the precious intellectual and technical advice, I owe my gratitude to the McGill Group for Suicide Studies, in particular to Dr. Chen Gang, Dr. Volodymyr Yerko, and Professor Gustavo Turecki. I also would like to thank all the members of the group for their readiness and enthusiasm to discuss their projects and share their scientific knowledge. Thanks to the Genomic Diversity Centre of the ETH Zurich, especially Silvia Kobel, Dr. Aria Minder, and Dr. Niklaus Zemp for assisting me in my sequencing experiments, and for all the funny moments we had in the lab. Finally, I would like to thank my friends and family. My warmest thank you goes to Vinita Jagannath, Adele Ferrari, Gian Marco Palamara, Alessandro Valentino, Nicolas Dorsaz, Livie Kundert, and Jürg Müller. Without these people by my side, it would have been impossible to ever complete this PhD thesis. Thank you for your patience and unceasing encouragement
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