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The Argonaute Family of Genes in Caenorhabditis Elegans: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2007-02-28 The Argonaute Family of Genes in Caenorhabditis Elegans: a Dissertation Erbay Yigit University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Amino Acids, Peptides, and Proteins Commons, Animal Experimentation and Research Commons, and the Nucleic Acids, Nucleotides, and Nucleosides Commons Repository Citation Yigit E. (2007). The Argonaute Family of Genes in Caenorhabditis Elegans: a Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/cgrp-qj08. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/328 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. THE ARGONAUTE FAMILY OF GENES IN CAENORHABDITIS ELEGANS A Dissertation Presented By ERBAY YİĞİT Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY FEBRUARY 28, 2007 PROGRAM IN MOLECULAR MEDICINE ii COPYRIGHT INFORMATION The chapters of this dissertation have appeared in seperate publications: Yigit, E.*, Batista, P.J.*, Bei, Y., Pang, K.M., Chen, C.C., Tolia, N.H., Joshua-Tor, L., Mitani, S., Simard, M.J., Mello, C.C (2006). Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell 17;127(4):747-57. *These authors contributed equally. iii APPROVAL PAGE THE ARGONAUTE FAMILY OF GENES IN CAENORHABDITIS ELEGANS A Dissertation Presented By Erbay Yiğit Approved as to style and content by: ___________________________________ Kirsten Hagstrom, Chair of Committee ___________________________________ Phillip D. Zamore, Member of Committee ___________________________________ Thoru Pederson, Member of Committee ___________________________________ Craig Peterson, Member of Committee ___________________________________ Keith Blackwell, Member of Committee _____________________________ Craig C. Mello, Dissertation Mentor __________________________________ Anthony Carruthers, Dean of the Graduate School of Biomedical Sciences Program in Molecular Medicine February 28, 2007 iv ACKNOWLEDGEMENTS I would like to thank Craig for giving me the opportunity to carry out my thesis research in his laboratory. I am grateful for his advice, valuable suggestions, and encouragement. I am thankful to all my colleagues and friends in the Mello lab for creating a stimulating and fun environment to do science. I especially want to thank postdocs Hiroaki Tabara and Ka Ming Pang for their help in the lab. In the course of my thesis research, I collaborated with Dr. Shohei Mitani, who generated the Argonaute deletion strains and Dr. Leemor Joshua-Tor and his postdoc Niraj Tolia, who made the phylogenetic tree of the Argonautes. I thank them all. For their time and valuable suggestions, I am grateful to the members of my thesis committee: Dr. Kirsten Hagstrom, Dr. Phillip Zamore, Dr. Thoru Pederson, Dr. Keith Blackwell, and Dr. Craig L. Peterson. I want to thank my dear friends in the Mello lab Julie and Daniel for proofreading my thesis. I especially want to thank Pedro and Yanxia for their intellectual and experimental contributions to my work. Finally I would like to thank my family: My father Yasar, my mother Sevinc, and my brothers Serbulent and Ercument. Thank you all for understanding me studying in another country far away from home, and supporting my decisions in life. v TABLE OF CONTENTS COPYRIGHT INFORMATION II APPROVAL PAGE III ACKNOWLEDGEMENTS IV TABLE OF CONTENTS V LIST OF FIGURES VIII LIST OF TABLES IX ABBREVIATIONS X ABSTRACT 1 CHAPTER I: GENERAL INTRODUCTION 3 The Discovery of RNAi 5 An Overview of the RNAi Pathway 8 Key Components and Steps in the RNAi Pathway 11 Dicer Proteins and Production of Small Interfering RNAs (siRNAs) 11 DsRNA Binding Proteins and Loading of the RISC with siRNAs 14 Effector Step of RNAi and Argonaute Family of Proteins 16 The PAZ Domain 17 The Piwi Domain 19 The RNAi Pathway in C. elegans 21 Initial Identification and Characterization of RNAi Deficient (rde) Mutants 21 Inheritance of RNAi 22 RNAi is Target-Dependent in C. elegans 23 Systemic RNAi 26 miRNA Pathway 29 Biogenesis of miRNAs 30 Mechanism of miRNA Silencing 31 Additional Classes of Small RNAs in C. elegans and Other Organisms 32 TncRNA, endo-siRNA and X-cluster siRNAs in C. elegans 32 vi 21U-RNA and 26-mer endo-siRNA in C. elegans 35 Repeat-Associated Small Interfering RNAs (rasiRNAs) 37 Piwi-interacting RNAs (piRNAs) 39 Enhancers of RNAi in C. elegans 40 RNAi and Antiviral Defense 44 RNAi, Co-suppression, Transgene, and Transposon Silencing 46 RNAi and Transcriptional Silencing 48 RNAi and Heterochromatin 51 RNAi and Genome Elimination 54 Introduction to My Thesis Research 56 CHAPTER II: ANALYSIS OF THE C. ELEGANS ARGONAUTE FAMILY REVEALS THAT DISTINCT ARGONAUTES ACT SEQUENTIALLY DURING RNAi 64 Summary 67 Introduction 68 Results 71 RDE-1 Interacts with Trigger-Derived Single-Stranded RNA 71 RDE-1 Does Not Interact with Secondary siRNAs 73 Genetic Analysis of Argonaute Mutants in C. elegans 77 Multiple Argonautes Contribute Incrementally to RNAi 78 Argonautes Required for RNAi Exhibit Qualitatively Distinct Activities 81 SAGO-1 and SAGO-2 Interact with Secondary siRNAs 81 An Endogenous Small RNA Pathway Requires ERGO-1 and SAGO Proteins 88 Discussion 90 Intersecting RNAi Pathways in C. elegans 96 AGOs and Transcriptional Gene Silencing 98 Material and Methods 105 CHAPTER III: ANALYSIS OF AN EIGHT-FOLD ARGONAUTE MUTANT (MAGO8) INDICATES THAT RNAI CONTRIBUTES TO THE vii MAINTENANCE OF STEM CELL TOTIPOTENCY IN C. ELEGANS 137 Summary 138 Results and Discussion 139 Future Experiments 145 Material and Methods 148 CHAPTER IV: GENERAL DISCUSSION 149 CHAPTER V: APPENDIX 157 BIBLIOGRAPHY 167 viii LIST OF FIGURES Figure I-1 Comparison of RNAi pathways in fly and worm 10 Figure I-2 Phylogenetic tree of Argonaute proteins 59 Figure II-1 Sequence specificity and genetics of RDE-1/RNA affinity matrix binding 75 Figure II-2 RDE-1 does not interact with secondary siRNAs 76 Figure II-3 Argonaute genes are required for RNAi and development 80 Figure II-4A SAGO-1 and SAGO-2 rescue the MAGO strain 85 Figure II-4BC SAGO-1 and SAGO-2 interact with secondary siRNAs 86 Figure II-4D siRNAs overaccumulate in overexprssing GFP::SAGO-1and GFP::SAGO-2 strains 87 Figure II-5 ergo-1 and the MAGO strain are deficient in endo-siRNA expression 89 Figure II-6 Model 92 Figure II-7 Secondary Argonautes lack key catalytic residues 94 Figure II-8 Argonaute deletion alleles 100 Figure II-9ABC Phenotypic analysis of Argonaute genes 102 Figure II-9D Analysis of RNAi defects by sequential dsRNA injection 103 Figure II-10 RNAi sensitivity in Argonaute multiple mutants 104 Figure II-11 Schematic representation of genetic crosses 128 Figure III-1 RNAi sensitivity of the MAGO8 Mutant 140 Figure III-2 Ectopic somatic cells in the germline of the MAGO8 strain 144 ix LIST OF TABLES Table II-1 Outcrossing Status of Argonaute Deletion Alleles 106 Table II-2 Strains Used in This Study 107 Table V-1 Primers Used for 5′ RACE Experiments 158 Table V-2 Primers Used To Make dsRNA 159 Table V-3 Argonaute Deletion Lesions 160 Table V-4 Primer Sequences Used in This Study 162 x ABBREVIATIONS CSR chromosome segregation and RNAi defective DCR-1 C. elegans Dicer protein DNA deoxyribonucleic acid DRH Dicer related helicase dsDNA double-stranded DNA dsRNA double-stranded RNA endo-RNAi endogenous RNAi ERGO endogenous RNAi deficient Argonaute ERI enhancer of RNAi exo-RNAi exogenous RNAi MAGO multiple-Argonaute mutant miRNA micro RNA mRNA messenger RNA piRNA Piwi-interacting RNA pre-miRNA miRNA precursor pri-miRNA primary miRNA rasiRNA repeat-associated small interfering RNA RDE RNAi defective RdRP RNA-dependent RNA polymerase RISC RNA-induced silencing complex RNA ribonucleic acid RNAi RNA-mediated interference or RNA interference RSD RNA spreading defective SAGO synthetic secondary-siRNA defective Argonaute siRNA short (small) interfering RNA ssDNA single-stranded DNA tncRNA tiny-noncoding RNA 1 ABSTRACT Members of the Argonaute family of proteins, which interact with small RNAs, are the key players of RNAi and other related pathways. The C. elegans genome encodes 27 members of the Argonaute family. During this thesis research, we sought to understand the functions of the members of this gene family in C. elegans. Among the Argonaute family members, rde-1 and alg-1/2 have previously been shown to be essential for RNAi and development, respectively. In this work, we wanted to assign functions to the remaining members of this large family of proteins. Here, we describe the phenotype of 31 deletion alleles representing all of the previously uncharacterized Argonaute members. In addition to rde-1, our analysis revealed that two other Argonaute members csr-1 and prg-1 are also essential for development. csr-1 is partially required for RNAi, and essential for proper chromosome segregation. prg-1, a member of PIWI subfamily of Argonaute genes, exhibits reduced brood size and temperature-sensitive sterile phenotype, implicating that it is required for germline maintenance. Additionally, we showed that RDE-1 interacts with trigger-derived sense and antisense siRNAs (primary siRNAs) to initiate RNAi, while several other Argonaute proteins, SAGO-1, SAGO-2, and perhaps others, functioning redundantly, interact with amplified siRNAs (secondary siRNAs) to mediate downstream silencing. Moreover, our analysis uncovered that another member of Argonaute gene family, ergo-1, is essential for the endogenous RNAi pathway. 2 Furthermore, we built an eight-fold Argonaute mutant, MAGO8, and analyzed its developmental phenotype and sensitivity to RNAi. Our analysis revealed that the genes deleted in the MAGO8 mutant function redundantly with each other, and are required for RNAi and the maintenance of the stem cell totipotency.
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