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154411902.Pdf The Role of MicroRNAs in Age-Related Disorders From population-based genetic studies to experimental validation Mohsen Ghanbari ACKNOWLEDGMEntS The research presented in this thesis was performed at Departments of Epidemiology and Immunology, Erasmus MC, Rotterdam, the Netherlands. The research was supported by a scholarship from the Ministry of Health and Medical Education in IRAN and Mashhad University of Medical Sciences (MUMS), and by Utzchit grant awarded to M. Meester-Smoor. The contribution of the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists is gratefully acknowledged. The Rotterdam Study is supported by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Publication of this thesis was kindly supported by the Department of Epidemiology and the Erasmus Medical Center Rotterdam, the Netherlands. Financial support was provided by Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Alzheimer Nederland and ChipSoft. Additional financial support by the Dutch Heart Foundation for the publica- tion of this thesis is gratefully acknowledged. ISBN: 978-94-92863-49-6 Layout, cover design and printing by Optima Grafische Communicatie Copyright © 2017 Mohsen Ghanbari, Rotterdam, the Netherlands No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission from the author of this thesis or, when appropriate, from the publishers of the manuscripts in this thesis. The Role of MicroRNAs in Age-Related Disorders From population-based genetic studies to experimental validation De rol van microRNAs in leeftijdsgerelateerde ziekten Van genetische populatiestudies naar experimentele validatie Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 5 juli 2017 om 13:30 uur Door Mohsen Ghanbari geboren te Mashhad, Iran Promotiecommissie Promotor: Prof.dr. O.H. Franco Overige leden: Prof.dr. C.C.W. Klaver Prof.dr. A. Uitterlinden Prof.dr. L. Franke Copromotors: Dr. A. Dehghan Dr. S. Erkeland Dr. M. Meester-Smoor Paranimfen: E. Sam Shokrollahi Lea Jasmina Jabbarian To my wife Sara and my son Shahrad And to my parents TABLE OF COntEntS Chapter 1 General introduction 8 Chapter 2 Contribution of microRNAs to cardiovascular risk factors 26 and disease 2.1 miR-4513 associates with multiple cardiometabolic traits and 29 diseases 2.2 Association of miR-196a2 with waist to hip ratio and miR-1908 51 with serum lipid and glucose 2.3 Genetic variants in miRNA-binding sites affect miRNA-mediated 71 regulation of cardiovascular genes 2.4 Genetic variants in long non-coding RNAs associate with 101 cardiometabolic disorders Chapter 3 Contribution of microRNAs to neurodegenerative diseases 134 3.1 Genome-wide identification of miRNA-related variants associated 137 with Alzheimer’s disease 3.2 Genetic variants in miRNAs and miRNA-binding sites are 157 associated with Parkinson’s disease 3.3 A genome-wide scan for long non-coding RNAs associated with 179 Alzheimer’s disease Chapter 4 Contribution of microRNAs to ophthalmic diseases 194 4.1 Genetic variants in miRNAs and their binding sites associate with 197 age-related macular degeneration (AMD) 4.2 Association of miRNA-related genetic variants with primary 227 open-angle glaucoma Chapter 5 General discussion 248 Chapter 6 Summary/ Samenvatting 272 Chapter 7 Appendices 280 Acknowledgements 283 PhD portfolio 287 List of publications 289 About the author 295 Chapter 1 General introduction General introduction 11 Recent developments in next-generation sequencing technologies have led to extensive transcriptome analysis of many human tissues and cell lines at an unprecedented scale. These data display that nearly the entire human genome has been transcribed, however, only a very small proportion (2%) of the transcripts are translated into protein products [1]. The rest of the transcripts that do not possess any protein-coding capacity are anno- tated as non-coding RNAs (ncRNAs). Over the past few years, it has become increasingly evident that ncRNAs act as important players in the epigenetic, post-transcriptional and translational coordination of gene expression in developmental processes and human diseases [2]. The ncRNAs can be roughly categorized, based on their transcript size, into two main classes: small ncRNAs (< 200 nucleotides) and long ncRNAs (> 200 nucleotides) [2, 3]. By far the best-characterized ncRNAs are microRNAs (miRNAs), which are the main focus of this thesis. MICRORNAS (MIRNAS) MiRNAs are a conserved class of small ncRNAs, spanning 20-24 nucleotides, that post- transcriptionally regulate gene expression at both messenger RNA (mRNA) and protein levels [4]. MiRNAs were discovered in C.elegans in the early 1990s, when Ambros and col- leagues observed that small RNA products from the heterochronic lin-4 gene regulated lin-14 gene expression by means of an RNA-RNA antisense pairing [5, 6]. However, not having homologs in other species, this RNA-based regulatory mechanism was thought to be unique to C.elegans until the second miRNA, let-7, was discovered with homo- logs in humans and Drosophila melanogaster [7, 8]. Since then, miRNAs have gained extensive attention as important modulators in diverse biological pathways, including stem cell differentiation, cell proliferation, apoptosis, and organ development, as well as being associated with a number of human diseases ranging from cancer to cardiovas- cular disease [9, 10]. The total number of confidently identified human miRNAs is now approximately 1,500 according to miRBase database (build 21), and around two-third of all coding genes in our genome are predicted to have at least one miRNA-binding site in their 3’UTR [11-14]. It was initially thought that human miRNAs are transcribed from ge- nomic regions quite distant from previously annotated genes, suggesting that they are generated as independent transcriptional units. However, later analyses of miRNA gene positions demonstrated that approximately 50% of human miRNAs are hosted within and co-transcribed with a protein-coding mRNA transcription unit. Thus, the expression of intronic miRNAs largely coincides with the transcription of the host gene [15]. Nearly 50% of miRNAs are clustered with one or more other miRNAs and are believed to be co-transcribed as a single polycistron by RNA Pol II enzyme in the nucleus [15]. 12 Chapter 1 miRNA BIOGENESIS In the canonical biogenesis pathway, miRNA genes are initially transcribed in the nucleus by the normal cellular machinery to yield a large RNA transcript, approximately 1000 nucleotides, containing an extended stem-loop structure called a primary miRNA (pri- miRNA) [16]. Two subsequent processing events lead to the functional, mature miRNA in animals. First, the RNase-III endonuclease enzyme, Drosha, coupled with the dsRNA- binding protein DiGeorge Syndrome critical region 8 (DGCR8), cleaves the pri-miRNA transcript into a smaller, ~70 nucleotides, hairpin precursor miRNA (pre-miRNA) [17, 18]. The pre-miRNA is then shuttled out of the nucleus through the Exportin 5 (XPO5) nuclear transport receptor in cooperation with a Ran GTPase cofactor [19]. After being transported to the cytoplasm, a second RNase-III enzyme (Dicer) cleaves the loop structure of the pre-miRNA, resulting in an approximately 22bp double-stranded miRNA [20]. The duplex miRNA is then dissociated and the passenger strand is degraded. Subsequently, the strand with the less thermodynamically stable 5’ end (guide strand) gets incorporated into the RNA-induced silencing complex (RISC) [21]. This active RISC complex, consisting of the mature miRNA and Argonaute (Ago) proteins, interacts with the 3’-untranslated region (3’UTR) of target mRNA. This results in either translational repression or site-specific cleav- age of target mRNAs, depending on the degree of complementarity to its target [14, 22]. An overall schematic of miRNA biogenesis and function is shown in Figure 1. miRNA-tarGET RECOGnitiON and REGULatORY FUNCtiON The core of a mature miRNA, called the “seed” sequence, includes nucleotides 2-7 (sometimes 2-8) from the 5’ end. This region of the miRNA is the most conserved among species and plays a critical role in target recognition and interaction [21]. The 3’-end of a miRNA modifies binding of the miRNA to its target genes and may compensate for seed mismatches [23]. Most miRNAs in animals are thought to control mRNA stability and trans- lation through imperfect base-pairing to the 3’UTR of target mRNAs [16, 21]. The most common mechanism through which a miRNA regulates its target gene expression is the binding of the miRNA seed sequence to the 3’UTR sequence of the target mRNA (Figure 2) [13, 21]. Other less common mechanisms that have been described include non-canonical sites, which display good base-pairing at both the 5’ and 3’ ends, and 3’ compensatory sites, which show weak 5’ base-pairing and depend on a strong pairing at the 3’ end [24]. The biological role of individual miRNAs is dictated by regulating their target mRNAs expression [21]. Given that miRNAs need only minimum binding by a short seed sequence, it is not surprising that a single miRNA targets multiple genes [13]. As a consequence, the accurate prediction of the miRNA target genes has been a great General introduction 13 Figure 1. The biogenesis of miRNAs is a multistep coordinated process. After transcription, the Drosha enzyme processes the long primary transcripts (pri-miRNA), yielding a hairpin precursors (pre-miRNA) con- sisting of approximately 70 nucleotides. The pre-miRNA hairpins are exported by Exportin 5 (XPO5) to the cytoplasm where they are further processed into unstable, 19-25 nucleotides miRNA duplex structures by the Dicer enzyme.
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