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UNIVERSITY of CALIFORNIA, SAN DIEGO Estrogen Signaling and The UNIVERSITY OF CALIFORNIA, SAN DIEGO Estrogen Signaling and the Circadian Clock Regulate the Kisspeptin Promoter A thesis submitted in partial satisfaction of the requirements of the degree Master of Science in Biology by Liza Eden Brusman Committee in charge: Pamela L. Mellon, Chair Susan S. Golden, Co-Chair Stanley M. Lo 2017 Copyright Liza Eden Brusman, 2017 All rights reserved. SIGNATURE PAGE The Thesis of Liza Eden Brusman is approved, and it is acceptable in quality and form for publication on microfilm and electronically. Co-Chair Chair University of California, San Diego 2017 iii EPIGRAPH It started out with a kiss, how did it end up like this? The Killers iv TABLE OF CONTENTS SIGNATURE PAGE ......................................................................................................... iii EPIGRAPH ........................................................................................................................ iv TABLE OF CONTENTS .....................................................................................................v LIST OF ABBREVIATIONS ............................................................................................ vi LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES ............................................................................................................. ix ACKNOWLEDGEMENTS .................................................................................................x ABSTRACT OF THE THESIS ......................................................................................... xi INTRODUCTION ...............................................................................................................1 The hypothalamic-pituitary-gonadal axis............................................................ 1 Kisspeptin signaling is required for pubertal onset and fertility ......................... 4 Estrogen signaling through ERα is required for the LH surge ............................ 5 Proper circadian rhythms are required for the LH surge ..................................... 8 Estrogen induces circadian oscillations in Kiss1 neurons ................................. 12 MATERIALS AND METHODS .......................................................................................15 Cell culture and treatments ................................................................................ 15 Plasmid constructs ............................................................................................. 15 Luciferase reporter assays ................................................................................. 16 LumiCycle ......................................................................................................... 17 Data analysis ..................................................................................................... 18 RESULTS ..........................................................................................................................19 The Kiss1 promoter contains 12 EREs and 5 E-boxes...................................... 19 Luciferase reporter assay optimization ............................................................. 22 Estrogen induction of the Kiss1 promoter requires ERα .................................. 30 Estrogen induces the Kiss1 promoter after 12 and 24 hours of estrogen treatment ............................................................................................................ 32 Kiss1 expression is dynamic only in the presence of estrogen ......................... 34 Per2 expression induces the Kiss1 promoter..................................................... 38 DISCUSSION ....................................................................................................................42 REFERENCES ..................................................................................................................48 v LIST OF ABBREVIATIONS ANOVA Analysis of variance ARC Arcuate nucleus AVP Arginine vasopressin AVPV Anteroventral periventricular nucleus βGal Beta-galactosidase BMAL1 Brain and muscle ARNT-like protein-1 Bp Base pairs CLOCK Circadian locomotor output cycles kaput CRY Cryptochrome CS Charcoal-stripped DMEM Dulbecco's modified eagle media E2 β-estradiol ERE Estrogen-response element ERα Estrogen receptor alpha ERβ Estrogen receptor beta EtOH Ethanol FBS Fetal bovine serum FSH Follicle-stimulating hormone GnRH Gonadotropin-releasing hormone GPR54 G protein-coupled receptor 54 HPG Hypothalamic-pituitary-gonadal Kb Kilobases Kiss1-luc pGL4.10-Kiss1-luc L-Glut L-Glutamine vi LH Luteinizing hormone Luc Luciferase Na-Pyruvate Sodium pyruvate P/S Penicillin/streptomycin PBS Phosphate-buffered saline PER Period Per2 Period 2 PR+ Phenol red-containing PR- Phenol red-free RLU Relative light units SCN Suprachiasmatic nucleus TSS Transcription start site vii LIST OF FIGURES Figure 1: Mammalian reproduction is controlled by the HPG axis. ................................... 3 Figure 2: ERα signaling mechanism. .................................................................................. 7 Figure 3: Schematic of the molecular circadian clock. ....................................................... 9 Figure 4: Schematic diagram of clocks within the brain. ................................................. 11 Figure 5: Schematic diagram of elements within the 4 kb Kiss1 promoter. ..................... 20 Figure 6: Optimization of phenol red................................................................................ 23 Figure 7: Serum shock optimization. ................................................................................ 26 Figure 8: Optimization of amount of ERα expression vector. .......................................... 28 Figure 9: E2 induction of the Kiss1 promoter is dependent on the expression of ERα. ... 31 Figure 10: Estrogen induces the Kiss1 promoter after 12 and 24 hours. .......................... 33 Figure 11: Analysis of Kiss1 promoter expression dynamics over the course of 5 days. 37 Figure 12: Optimization of total amount of Per2 expression vector. ................................ 39 Figure 13: Per2 induces the Kiss1 promoter. .................................................................... 41 viii LIST OF TABLES Table 1: Locations of elements within the Kiss1 promoter. ............................................. 21 ix ACKNOWLEDGEMENTS I would like to thank Dr. Pamela Mellon for her support and guidance during the three years that I worked in the Mellon lab. She has been an invaluable resource throughout my time in the lab. I would also like to thank the other members of my thesis committee, Dr. Susan Golden and Dr. Stanley Lo, for their feedback on my project. I want to give a special thank you to Dr. Polly Huang who mentored me during my earliest days in the lab and continues to support me and my scientific career. She had endless patience teaching me how to pipette and taught me how to work in a lab. I am especially grateful to Dr. Karen Tonsfeldt for her endless support and patience through this entire process. Her wisdom and insight has shaped my identity as a scientist and helped me develop my love for research and biology. The compassion she has shown me and her belief in me has truly helped me grow as a person. Finally, I’d like to thank all the members of the Mellon lab for being in my corner and wanting me to succeed. x ABSTRACT OF THE THESIS Estrogen Signaling and the Circadian Clock Regulate the Kisspeptin Promoter by Liza Eden Brusman Master of Science in Biology University of California, San Diego, 2017 Professor Pamela L. Mellon, Chair Professor Susan S. Golden, Co-Chair The luteinizing hormone (LH) surge, which prompts ovulation, is dependent on the coincidence of multiple molecular cues. Specifically, estrogen signaling and circadian rhythms work together to gate the LH surge. Although previous studies have shown that the absence of either the estrogen receptor α (ERα) or the circadian clock results in anovulation, the mechanisms behind these regulatory components are not well xi understood. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) initiate the cascade of hormones that ultimately cause the LH surge, and it is thought that these neurons are the location of integration of ERα and circadian rhythm signaling. In this study, we sought to elucidate mechanisms by which ERα signaling and circadian rhythms regulate the expression of the Kiss1 promoter. We found that estrogen induces the Kiss1 promoter after both 12 and 24 hours of treatment, and that this induction is dependent on the expression of ERα. On a finer temporal scale, estrogen-induced Kiss1 promoter expression may be dynamic in vitro , but the expression pattern is not circadian, indicating that estrogen signaling through ERα alone is not sufficient to drive circadian expression of Kiss1 . We also found that the molecular clock protein Period 2 (Per2) is capable of inducing the Kiss1 promoter. Taken together, these data indicate that ERα and Per2 regulate the Kiss1 promoter and may be involved in the temporally controlled, estrogen-dependent LH surge. xii INTRODUCTION Ovulation, and thus fertility, depends on the precise orchestration of hormonal and temporal cues. The preovulatory hormone surge that is required to prompt ovulation is gated by two components: estrogen and circadian time. In humans and rodents, the preovulatory luteinizing hormone
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