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Dissecting the Genetic Etiology of Lupus at ETS1 Locus

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Dissecting the Genetic Etiology of Lupus at ETS1 Locus A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Immunobiology of the College of Medicine 2017 by Xiaoming Lu B.S. Sun Yat-sen University, P.R. China June 2011 Dissertation Committee: John B. Harley, MD, PhD Harinder Singh, PhD Leah C. Kottyan, PhD Matthew T. Weirauch, PhD Kasper Hoebe, PhD Lili Ding, PhD i Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong evidence for genetics factor involvement. Genome-wide association studies have identified 84 risk loci associated with SLE. However, the specific genotype-dependent (allelic) molecular mechanisms connecting these lupus-genetic risk loci to immunological dysregulation are mostly still unidentified. ~ 90% of these loci contain variants that are non-coding, and are thus likely to act by impacting subtle, comparatively hard to predict mechanisms controlling gene expression. Here, we developed a strategic approach to prioritize non-coding variants, and screen them for their function. This approach involves computational prioritization using functional genomic databases followed by experimental analysis of differential binding of transcription factors (TFs) to risk and non-risk alleles. For both electrophoretic mobility shift assay (EMSA) and DNA affinity precipitation assay (DAPA) analysis of genetic variants, a synthetic DNA oligonucleotide (oligo) is used to identify factors in the nuclear lysate of disease or phenotype-relevant cells. This strategic approach was then used for investigating SLE association at ETS1 locus. Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated Ets1 as a critical driver of immune cell function and differentiation, and mice deficient in Ets1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed ii each of these variants based on their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we have experimentally examined, only rs6590330 differentially binds lysate from B cells in EMSA. Using DAPA- mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci (eQTL) indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1. However, whether this differential gene expression caused by rs6590330 is biologically relevant or not has not been answered. We then developed a system combining the Clustered regularly interspaced short palindromic repeats (CRISPR) Homology-directed Repair technique with Tet-inducible Controlled Gene Expression technique to precisely control gene expression, which can mimic this differential gene expression caused by genetic variants. The investigation of this small differential gene expression may make important progress in the field of human genetics and especially the complex genetic disease etiology of SLE. iii iv Acknowledgements This work was supported in part by grants from Dr. John Harley and Dr. Leah Kottyan, and Ryan Fellowship granted to XL. I would also like to thank the Center for Autoimmune Genomics and Etiology (CAGE) department and the Immunobiology graduate program at CCHMC for stipend support, technical support, intellectual training, experimental reagents and research space. I would like to thank my mentor, Dr. John Harley, for dedicating his time, energy and resources for my scientific training. He always came up with amazing ideas for research. He taught me about how to think the science in a big way and how to develop a good grant. Meanwhile, he tried to make me think about what kind of researcher I want to be in the future and what kind of risk I would like to take for the research. Importantly, he allowed me to explore myself to find my own interest, which gives me the great confidence to be an independent researcher. I would also like to thank Dr. Leah Kottyan for her mentoring. She is extraordinary nice, patient and responsible. As a graduate student from non-coding background, she patiently taught me about how to do the genetic analysis. As an international student, she taught me the meaning of presentation and how to prepare that. As a trainee, she helped me to plan and interpret experiments. Importantly, she facilitated my success through promoting my understanding of professional development. We worked very closely to tackle scientific questions and make research plans. Apart from our work in the lab, Dr. Leah Kottyan has been an amazing life mentor. She has been an amazing model for how to balance life and science. I am truly blessed to have her as a mentor, and I do not plan to leave her mentorship as I move on professionally. v In addition to Dr. John Harley and Dr. Leah Kottyan, I really thank the rest of my dissertation and qualifier committee members: Dr. Harinder Singh, Dr. Matthew T. Weirauch, Dr. Kasper Hoebe, Dr. Lili Ding, Dr. Ken Greis and Dr. Iouri Chepelev. Friends and colleagues have all been invaluable for my graduate study. They helped me to keep strong and confident as international students. Guansheng Liu is especially important to me. He treated me as a brother and helped me to settle down everything in the USA. I deeply appreciated his help during the way. Also, Bo Liu, Coco Liu, Yuan Li, Shiyu Zhou, Erin Zoller and Carolyn Rydyznski are important support to me. They helped me enjoy the scientific life and social life in the USA. Meanwhile, Zubin Patel and Erin Zoller are my close research friends. Since we worked on similar projects, it was really good to discuss science with them. In the end, I really need to thank my family for their sacrifice, understanding, and support during this process. My wife, Chen, has great confidence in my ability to become a successful scientist. She is nice and beautiful. She always has a way to help me live a happy life. We together have a wonderful time in the USA. I would also appreciate the support from my family in China. They worked so hard to provide me with the opportunity to explore myself. They taught me about how to be a person valuable to the society. They are always willing to help me with their best. I really miss them and am sorry for not being able to accompany them for these five years. I hope the best for my family. vi Table of Contents Title ....................................................................................................................................... i Abstract ................................................................................................................................ ii Acknowledgements ............................................................................................................... v Table of Contents ................................................................................................................ vii Chapter 1. Background and Introduction................................................................................ 1 The Immune System in Health and Disease .....................................................................................2 Systemic Lupus Erythematosus Introduction ...................................................................................4 Clinical Features of SLE ......................................................................................................................... 4 Diagnostic Criteria/Criteria for Inclusion in Research .......................................................................... 5 Pathoetiology of SLE ............................................................................................................................. 6 Role of B-Cells in SLE Pathogenesis ...................................................................................................... 8 Cytokines in SLE .................................................................................................................................... 9 Immune Cell Dysfunction in SLE ......................................................................................................... 14 Toll-Like Receptors (TLRs) in SLE ........................................................................................................ 19 Complement System in SLE ................................................................................................................ 21 SLE Animal Models ............................................................................................................................
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