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Long Noncoding Rnas Are Critical Regulators of Pancreatic Islet Development and Function

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Long Noncoding Rnas Are Critical Regulators of Pancreatic Islet Development and Function Long noncoding RNAs are critical regulators of pancreatic islet development and function Ruth A. Singer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2018 Ruth A. Singer All rights reserved ABSTRACT Long noncoding RNAs are critical regulators of pancreatic islet development and function Ruth A. Singer Diabetes is a complex group of metabolic disorders with genetic, immunological, and environmental etiologies. Decades of diabetes research have elucidated many genetic drivers of normal islet function and dysfunction. Furthermore, genome wide associated studies (GWAS) have discovered that most diabetes susceptibility loci fall outside of coding regions, which suggests a role for noncoding elements in the development of disease. This highlights our incomplete understanding of the islet regulome and suggests the need for detailed functional analyses of noncoding genes to precisely determine their contribution to diabetes susceptibility and disease progression. Transcriptome analyses have revealed that the eukaryotic genome is pervasively transcribed. Strikingly, only a small proportion of the transcriptome is subsequently translated into protein; the majority is made up non-protein coding RNAs (ncRNAs). The most abundant class of these ncRNAs are called long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides that lack protein-coding potential. The establishment of lncRNAs, once dismissed as genomic dark matter, as essential gene regulators in many biological processes has redefined the central role for RNA in cells. While evidence suggests a role for lncRNAs in islets and diabetes, in vivo functional characterization of islet lncRNAs is lacking. For my thesis project, I sought to understand the lncRNA regulatory mechanisms that promote pancreas development and function. We conducted comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets and identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors. One of the candidate lncRNAs, Pax6 Upstream Antisense RNA (Paupar), mapped near Pax6, a gene encoding an essential pancreatic regulatory protein. We demonstrate Paupar is enriched in glucagon-producing alpha cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential alpha cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of Pax6 alpha cell target genes and corresponding alpha cell dysfunction. These findings illustrate a distinct mechanism by which lncRNAs can contribute to cell-specific regulation of broadly expressed transcription factors to coordinate critical functions within a cell. TABLE OF CONTENTS LIST OF FIGURES AND TABLES..............................................................................................iv LIST OF ABBREVIATIONS.......................................................................................................vii ACKNOWLEDGEMENTS............................................................................................................xi DEDICATION..............................................................................................................................xiii CHAPTER 1: Introduction I. Pancreatic islet development........................................................................................................1 Pancreas anatomy................................................................................................................1 Specification of pancreatic progenitor cells........................................................................5 Differentiation of pancreatic progenitor cells.....................................................................6 Specification of pancreatic endocrine progenitor cells.......................................................7 Differentiation pancreatic endocrine progenitor cells........................................................8 Alpha and Beta cell specification and maturation.............................................................14 Cell specific function of pancreatic transcription factors.................................................14 II. Pancreatic islet function............................................................................................................19 Bihormonal regulation of glucose homeostasis.................................................................19 Beta cells and insulin.........................................................................................................19 Alpha cells and glucagon...................................................................................................22 III. Islet dysfunction and diabetes..................................................................................................27 Health burden....................................................................................................................27 Pathophysiology of islet dysfunction.................................................................................28 Current treatments.............................................................................................................39 Beta cell replacement therapy...........................................................................................31 i Genetic factors contributing to diabetes............................................................................37 IV. Noncoding RNAs.....................................................................................................................39 Regulatory noncoding RNAs..............................................................................................39 MicroRNAs in beta cell development and function............................................................39 Long noncoding RNAs.......................................................................................................46 V. Islet long noncoding RNAs.......................................................................................................48 A role for long noncoding RNAs in diabetes.....................................................................48 Identification of islet long noncoding RNAs......................................................................50 Expression patterns of islet long noncoding RNAs............................................................52 Functional characterization of islet lncRNAs....................................................................55 Molecular characterization of islet lncRNAs.....................................................................57 Summary and thesis aims...................................................................................................60 CHAPTER 2: The lncRNA Paupar confers cell specific regulatory functions on Pax6 via alternative splicing.........................................................................................................................63 Summary............................................................................................................................63 Introduction........................................................................................................................64 Materials and Methods......................................................................................................68 Results................................................................................................................................79 Discussion..........................................................................................................................90 CHAPTER 3: Conclusions and Future Perspectives...................................................................133 The lncRNA Paupar.........................................................................................................133 Noncoding RNAs..............................................................................................................134 Noncoding RNAs and Species Complexity.......................................................................136 ii LncRNAs, transcription factors, and alternative splicing...............................................137 Future Directions.............................................................................................................141 Concluding Remarks........................................................................................................143 REFERENCES............................................................................................................................144 APPENDIX: Identification of alternatively spliced genes in alpha versus beta cell human and mouse transcriptomes...................................................................................................................177 Introduction......................................................................................................................177 Results..............................................................................................................................178 Discussion........................................................................................................................178 Methods............................................................................................................................179
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