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Genetic Regulation of Tmem106b in the Pathogenesis of Frontotemporal Lobar Degeneration

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Genetic Regulation of Tmem106b in the Pathogenesis of Frontotemporal Lobar Degeneration University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration Michael Gallagher University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Genetics Commons, Molecular Biology Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Gallagher, Michael, "Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration" (2017). Publicly Accessible Penn Dissertations. 2294. https://repository.upenn.edu/edissertations/2294 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2294 For more information, please contact [email protected]. Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration Abstract Neurodegenerative diseases are an emerging global health crisis, with the projected global cost of dementia alone expected to exceed $1 trillion, or >1% of world GDP, by 2018. However, there are no disease-modifying treatments for the major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis. Therefore, there is an urgent need for a better understanding of the pathophysiology underlying these diseases. While genome-wide association studies (GWAS) have identified ~200 genetic ariantsv that are associated with risk of developing neurodegenerative disease, the biological mechanisms underlying these associations are largely unknown. This dissertation investigates the mechanisms by which common genetic variation at TMEM106B, a GWAS-identified risk locus for FTLD, influences disease risk. First, using genetic and clinical data from thirty American and European medical centers, I demonstrate that the TMEM106B locus acts as a genetic modifier of a common Mendelian form of FTLD. Second, I investigate the role of increased TMEM106B expression levels, which have been reported both in FTLD patients and in individuals carrying the TMEM106B risk allele, in FTLD pathogenesis. I demonstrate that microRNA-132, the most dysregulated microRNA in a genome-wide screen of FTLD and control brains, directly represses TMEM106B expression in human cells, and likely contributes to the elevated TMEM106B levels seen in disease. I then combine statistical approaches, bioinformatics, and experimental approaches in order to functionally characterize all candidate GWAS causal variants at the TMEM106B locus. This approach identifies a noncoding variant, rs1990620, which affects CTCF- mediated long-range chromatin interactions between distal regulatory elements, as the likely causal variant responsible for altering TMEM106B expression levels and disease risk. These results provide a plausible mechanism by which TMEM106B genotype and expression levels influence FTLD risk and clinical progression, and provide a general framework for elucidating the biological mechanisms underlying a disease-associated risk locus. Such an approach will be necessary in order to translate the thousands of loci associated with disease risk by GWAS into mechanistic understanding and therapeutic advances. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Alice S. Chen-Plotkin Keywords CTCF, eQTL, frontotemporal dementia, frontotemporal lobar degeneration, GWAS, TMEM106B Subject Categories Genetics | Molecular Biology | Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2294 GENETIC REGULATION OF TMEM106B IN THE PATHOGENESIS OF FRONTOTEMPORAL LOBAR DEGENERATION Michael D. Gallagher 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 2017 Supervisor of Dissertation _______________________________ Alice S. Chen-Plotkin, M.D. Associate Professor of Neurology Graduate Group Chairperson _______________________________ Daniel S. Kessler, Ph.D. Associate Professor of Cell and Developmental Biology Dissertation Committee Nancy M. Bonini, Ph.D., Florence R.C. Murray Professor of Biology Christopher D. Brown, Ph.D., Assistant Professor of Genetics Maja Buĉan, Ph.D., Professor of Genetics (committee chair) Stephen A. Liebhaber, M.D., Professor of Genetics Daniel J. Rader, M.D., Seymour Gray Professor of Molecular Medicine DEDICATION I would like to dedicate this dissertation to my wife (Rachael), mother (Lindsay), father (Robert), and brother (Kevin), who are a constant source of love and support. I am so grateful to have such a wonderful family, without which I would not have been able to pursue all the things that I love. ii ACKNOWLEDGMENTS This dissertation is a result of the outstanding mentorship I received from Dr. Alice S. Chen- Plotkin. She has displayed incredible passion and devotion to my scientific training, and consistently provided invaluable guidance and support during my tenure in her lab. I have also benefited from an outstanding thesis committee, consisting of Drs. Nancy M. Bonini, Christopher (Casey) D. Brown, Maja Buĉan, Stephen A. Liebhaber, and Daniel J. Rader, with whom I met once per year during the dissertation phase of my thesis. Every meeting provided unique and important guidance, advice, and feedback. I would also like to thank the faculty and administration of the Cell & Molecular Biology (CAMB) Graduate Group and the Genetics & Gene Regulation (GGR) program, for constantly taking time out of their busy schedules to help graduate students in every phase of their training. Specifically, I would like to acknowledge Drs. Daniel S. Kessler and Douglas J. Epstein, the chairpersons of CAMB and GGR at the time of my matriculation, respectively, and Meagan Schofer, Anna Kline, and Kathy O’Connor-Cooley, the CAMB administrators. Finally, I would like to thank all past and present members of the Chen-Plotkin lab for their input, advice, and contributions. iii ABSTRACT GENETIC REGULATION OF TMEM106B IN THE PATHOGENESIS OF FRONTOTEMPORAL LOBAR DEGENERATION Michael D. Gallagher Alice S. Chen-Plotkin Neurodegenerative diseases are an emerging global health crisis, with the projected global cost of dementia alone expected to exceed $1 trillion, or >1% of world GDP, by 2018. However, there are no disease-modifying treatments for the major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis. Therefore, there is an urgent need for a better understanding of the pathophysiology underlying these diseases. While genome-wide association studies (GWAS) have identified ~200 genetic variants that are associated with risk of developing neurodegenerative disease, the biological mechanisms underlying these associations are largely unknown. This dissertation investigates the mechanisms by which common genetic variation at TMEM106B, a GWAS-identified risk locus for FTLD, influences disease risk. First, using genetic and clinical data from thirty American and European medical centers, I demonstrate that the TMEM106B locus acts as a genetic modifier of a common Mendelian form of FTLD. Second, I investigate the role of increased TMEM106B expression levels, which have been reported both in FTLD patients and in individuals carrying the TMEM106B risk allele, in FTLD pathogenesis. I demonstrate that microRNA-132, the most dysregulated microRNA in a genome-wide screen of FTLD and control brains, directly represses TMEM106B expression in human cells, and likely contributes to the elevated TMEM106B levels seen in disease. I then combine statistical approaches, bioinformatics, and experimental approaches in order to functionally characterize all candidate GWAS causal variants at the TMEM106B locus. This approach identifies a noncoding variant, rs1990620, which affects CTCF-mediated long-range chromatin interactions between distal regulatory elements, as iv the likely causal variant responsible for altering TMEM106B expression levels and disease risk. These results provide a plausible mechanism by which TMEM106B genotype and expression levels influence FTLD risk and clinical progression, and provide a general framework for elucidating the biological mechanisms underlying a disease-associated risk locus. Such an approach will be necessary in order to translate the thousands of loci associated with disease risk by GWAS into mechanistic understanding and therapeutic advances. v TABLE OF CONTENTS DEDICATION ................................................................................................................. II ACKNOWLEDGMENTS.................................................................................................III ABSTRACT................................................................................................................... IV LIST OF TABLES ......................................................................................................... IX LIST OF ILLUSTRATIONS ............................................................................................ X PREFACE .................................................................................................................... XII CHAPTER 1: INTRODUCTION .....................................................................................
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