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NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer

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Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 11-7-2018 Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer Jairo Ramos [email protected] Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Clinical Epidemiology Commons Recommended Citation Ramos, Jairo, "Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer" (2018). FIU Electronic Theses and Dissertations. 3872. https://digitalcommons.fiu.edu/etd/3872 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida DECIPHER MECHANISMS BY WHICH NUCLEAR RESPIRATORY FACTOR ONE (NRF1) COORDINATES CHANGES IN THE TRANSCRIPTIONAL AND CHROMATIN LANDSCAPE AFFECTING DEVELOPMENT AND PROGRESSION OF INVASIVE BREAST CANCER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PUBLIC HEALTH by Jairo Ramos 2018 To: Dean Tomás R. Guilarte Robert Stempel College of Public Health and Social Work This dissertation, Written by Jairo Ramos, and entitled Decipher Mechanisms by Which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read the dissertation and recommend that it be approved. ___________________________________________ Alok Deoraj ___________________________________________ Juan Luizzi ___________________________________________ Quentin Felty __________________________________________ Deodutta Roy, Co-Major Professor __________________________________________ ChangWon Yoo, Co-Major Professor Date of Defense: November 7, 2018 The dissertation of Jairo Ramos is approved. ___________________________________________ Dean Tomás R. Guilarte R. Stempel College of Public Health and Social Work ___________________________________________ Andres G. Gil Vice President for Research and Economic Development and Dean of the University Graduate School Florida International University, 2018 ii © Copyright 2018 by Jairo Ramos All rights reserved. iii DEDICATION This dissertation is dedicated to the memory of my parents, Raul Ramos and Elinor Vega de Ramos, Who alWays encouraged me to pursue my dreams through education; to the memory of my sister, Meibis Ramos, who was alWays there for me through the good and bad times; and to my Wife, Mile, and my two sons, Jairo and Andres, Who Were my inspiration to pursue my doctoral degree. iv ACKNOWLEDGMENTS I Would like to thank first my major professor, Dr. Deodutta Roy, for his continuous support and patience and for sharing With me all his knoWledge in the fields of genetics, epigenetics, and carcinogenesis. I have learned a great deal from him. The research and Writing of this dissertation Would have not been possible Without his help and guidance. I Wish to thank my co-major professor, Dr. ChangWon Yoo, for his assistance and support in the field of biostatistics and for facilitating the tools (hardWare and softWare) I needed for the statistical analysis section of my research. I also Want to express my gratitude to the other members of my dissertation committee: Dr. Quentin Felty, Dr. Alok Deoraj, and Dr. Juan Liuzzi, for their encouragement, comments, and suggestions that helped me to complete successfully this dissertation. I thank too my felloW students from the Environmental Health Science Department and from the SMLG group for the stimulating discussions and camaraderie and for sharing With me their knoWledge in different fields of health sciences and statistics. My thanks also to Marie Alvarez, our former departmental secretary, who helped me greatly With all the administrative matters and the use of the university’s resources. My sincere gratitude goes to the Starr Foundation for its generosity and to the committee members at Stempel College Who selected me as one of the recipients of the STARR scholarship in 2016 and 2017. v Last but not least, I Would like to thank my brother, Dr. Ariel Ramos, and my nepheW, Larry Ramos, for their continuous support and encouragement while I pursued my dream of becoming a scientist. vi ABSTRACT OF THE DISSERTATION DECIPHER MECHANISMS BY WHICH NUCLEAR RESPIRATORY FACTOR ONE (NRF1) COORDINATES CHANGES IN THE TRANSCRIPTIONAL AND CHROMATIN LANDSCAPE AFFECTING DEVELOPMENT AND PROGRESSION OF INVASIVE BREAST CANCER by Jairo Ramos Florida International University, 2018 Miami, Florida Professor Deodutta Roy, Co-Major Professor Professor ChangWon Yoo, Co-Major Professor Despite tremendous progress in the understanding of breast cancer (BC), gaps remain in our knoWledge of the molecular basis underlying the aggressiveness of BC and BC disparities. Nuclear respiratory factor 1 (NRF1) is a transcription factor (TF) knoWn to control breast cancer cell cycle progression. DNA response elements bound by NRF1 positively correlate With the progression of malignant breast cancer. Mechanistic aspects by Which NRF1 contributes to susceptibility to different breast tumor subtypes are still not fully understood. Therefore, the primary objective of this dissertation was to decipher mechanisms by Which NRF1 coordinates changes in the transcriptional and chromatin landscape affecting development and progression of invasive breast cancer. Our hypothesis was that NRF1 reprogramming the transcription of tumor initiating gene(s) and tumor suppressor gene(s) contribute in the development and progression of vii invasive breast cancer. To test this hypothesis, We proposed three specific aims: (a) Decipher regulatory landscape of NRF1 netWorks in breast cancer. (b) Determine the role of NRF1 gene netWorks in different subtypes of breast cancer. (c) Determine differential NRF1 gene netWork sensitivity contributing to breast cancer disparities. Our approach to test these aims consisted of a systematic integration of ChIP DNA-seq, RNA-Seq, NRF1 protein-DNA motif binding, signal pathWay analysis, and Bayesian machine learning. We uncovered a novel oncogenic role for NRF1. This discovery strongly supported the supposition that NRF1 overexpression is sufficient to derive breast tumorigenesis. We also observed neW roles for NRF1 in the acquisition of breast tumor initiating cells, regulation of epithelial to mesenchymal transition (EMT), and invasiveness of BC stem cells. Furthermore, through the use of Bayesian netWork structure learning we found that the NRF1 motif Was enriched in 14 associated With HER2 amplified breast cancer. Three genes—GSK3B, E2F3, and PIK3CA—Were able to predict HER2 breast tumor status With 96% to100% confidence. The findings of this study also shoWed the roles of NRF1 sensitivity to development of lobular A, Her2+, and TNBC in different racial/ethnic groups of breast cancer patients. In summary, our study revealed for the first time the role of NRF1 in the pathogenesis of invasive BC and BC disparities. viii TABLE OF CONTENTS CHAPTER PAGE I. INTRODUCTION ............................................................................................. 1 Overall Goal ................................................................................................ 5 Hypothesis and Specific Aims .................................................................... 5 REFERENCES ........................................................................................... 6 II. CURRENT KNOWLEDGE OF NRF1 INVOLVEMENT IN THE PATHOGENESIS OF BREAST CANCER, INCLUDING GENE ONTOLOGY AND PATHWAY ANALYSIS OF NRF1 REGULATED NETWORKS .................................................................................................... 9 Abstract....................................................................................................... 9 Introduction ............................................................................................... 10 Results and Discussion ............................................................................ 12 Conclusion ................................................................................................ 78 Methods .................................................................................................... 78 REFERENCES ......................................................................................... 79 III. INTEGRATED CHIP-SEQ AND RNA-SEQDATA ANALYSIS TO INVESTIGATE REGULATORY MECHANISMS OF NRF1 TRANSCRIPTION FACTOR ON TARGET GENES IN HER2+ BREAST CANCER CELLS ........................................................................................... 86 Abstract..................................................................................................... 86 Introduction ............................................................................................... 87 Methods .................................................................................................... 88 Results and Discussion .........................................................................
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