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Comprehensive understanding of the determinants for functional microRNA targeting : 마이크로RNA의 기능적인 표적 조절 인자의 포괄적인 이해
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 백대현 | - |
dc.contributor.author | 김도연 | - |
dc.date.accessioned | 2021-11-30T04:46:32Z | - |
dc.date.available | 2022-03-28T21:00:24Z | - |
dc.date.issued | 2021-02 | - |
dc.identifier.other | 000000164000 | - |
dc.identifier.uri | https://hdl.handle.net/10371/175963 | - |
dc.identifier.uri | https://dcollection.snu.ac.kr/common/orgView/000000164000 | ko_KR |
dc.description | 학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 생명과학부, 2021. 2. 백대현. | - |
dc.description.abstract | MicroRNAs (miRNAs) are key regulators of metazoan gene expression and are estimated to directly regulate >60% of human mRNAs. miRNAs are involved in numerous biological processes, and abnormality in miRNA-mediated gene regulation can lead various diseases. The mechanism by which miRNAs recognize their targets and downregulate the expression levels of the targets is referred to as miRNA targeting (MT). In spite of the efforts made by researchers, only a limited portion of the regulatory outcome of MT on transcriptome can be described with current knowledge. In this work, we aim to reveal key determinants responsible for effective MT in comprehensive perspective. In the first part of the thesis, we focus on identification of general rules for functional MT. Accordingly, we suggest seven non-canonical functional site types identified by examining >2 billion site types between mRNAs and miRNAs. In the second part of the thesis, we suggest hundreds of RNA-binding proteins (RBPs) as major determinants of MT. With systematic analyses of large-scale transcriptome datasets and binding maps of various RBPs, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers. With illuminating the unappreciated regulatory impact of the non-canonical site types and RBP binding, our findings are expected to provide a more comprehensive insight into the complex gene regulatory network governed by MT. | - |
dc.description.abstract | 마이크로RNA (miRNA)는 후생동물의 유전자 발현에 핵심적인 조절자 역할을 하며, >60%의 인간 mRNA들이 miRNA의 조절을 받는 것으로 알려져 있다. miRNA는 다양한 생물학적 과정에 관여하며, miRNA에 의한 유전자 발현 조절의 이상은 다양한 질병을 일으킬 수 있다. miRNA가 표적을 인식하고 이들의 발현을 억제하는 일련의 기작을 miRNA 타겟팅 (MT)이라고 일컫는다. 그러나, MT에 의한 유전자 조절 효과에 영향을 미치는 인자에 대해서 밝혀진 바가 부족한 실정이다. 본 학위논문에서는 효과적인 MT에 기여하는 주요 인자들을 포괄적으로 동정 및 규명하는 것을 목표로 한다. 논문의 첫번째 장에서는, 기능적인 MT를 유발하는 일반적인 규칙을 발굴하는 데에 초점을 맞춘다. miRNA와 mRNA 사이의 >20억 개의 결합 규칙에 대해 조사한 결과, 7가지의 비표준적 결합규칙이 기능적으로 MT를 유발할 수 있음을 밝힌다. 논문의 두번째 장에서는, 수백 가지의 RNA-결합 단백질 (RBP)들이 MT 효율의 주요 결정인자로 동작함을 제안한다. 대규모의 전사체 데이터와 RBP 결합 정보를 분석하여, 대부분의 RBP들이 MT의 촉진자로 기능함을 규명한다. 본 연구는 그간 간과되어온 비표준적 결합 규칙과 RBP 결합이 MT 효율에 미치는 영향을 규명함으로써, MT에 의해 제어되는 복잡한 유전자 조절 네트워크를 이해함에 있어 보다 포괄적인 시각을 제공할 것으로 기대된다. | - |
dc.description.tableofcontents | Abstract 1
List of Figures and Tables 6 Chapter I. Introduction Background 8 Canonical site types (CSTs) 8 Previously reported noncanonical site types (NSTs) 10 Systematic evaluation of previously reported NSTs 13 Determinants of miRNA targeting efficacy 14 Purpose of this study 15 Chapter II. General rules for functional microRNA targeting. Introduction 18 Experimental Procedures 21 Selection of reference mRNAs 21 Compilation of the site types 21 Construction of the analysis pipeline for discovery of functional site types 23 Detection of functional NST candidates 28 Detection of functional context-dependent NST candidates 29 Luciferase reporter assay 30 Validation analyses using independent microarray data 31 Evolutionary conservation of the NSTs and CDNSTs 32 Estimation of the amount of overall mRNA regulation 33 Results 34 A large number of interactions are predicted to occur between human miRNAs and mRNAs 34 Construction of analysis pipeline and evaluation of detection sensitivity 35 Detection of functional NST candidates 36 Detection of context-dependent functional NST candidates 41 Validation of novel NSTs and CDNSTs 45 The impact of functional miRNA targeting on mRNA repression 53 Discussion 56 Chapter III. Widespread regulatory impact of RNA-binding proteins on microRNA targeting. Introduction 60 Experimental Procedures 62 Selection of reference mRNAs 62 Processing of RBP-binding information of eCLIP-seq data 62 Preprocessing and alignment of sequenced reads 63 Selection of miRNAs for overexpression experiments 65 mRNA-seq data processing 65 Correction for potentially confounding features of miRNA targeting 67 Association analysis between the number of RBPs binding close to the miRNA target site and miRNA targeting efficacy 68 Examination on motif-specific RBP-binding sites 70 Transcriptome-wide analysis for global impact of RBPs on miRNA targeting 70 Assessment of global impact of RBPs on miRNA targeting 71 Examination on co-occurrence of miRNA target sites and RBP-binding sites 72 Results 74 RBP binding enhances miRNA targeting 74 Most RBPs are miRNA targeting enhancers 78 A potential mechanism by which RBP binding enhances miRNA targeting 83 Widespread regulatory impact of RBPs on miRNA targeting 91 Discussion 94 Chapter IV. Conclusion 96 References 99 Abstract in Korean (국문초록) 112 | - |
dc.format.extent | 113 | - |
dc.language.iso | eng | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | microRNA | - |
dc.subject | targeting | - |
dc.subject | siRNA | - |
dc.subject | computational biology | - |
dc.subject | bioinformatics | - |
dc.subject | transcriptome | - |
dc.subject | RNA-binding protein | - |
dc.subject | 마이크로RNA (miRNA) | - |
dc.subject | 타겟팅 | - |
dc.subject | 전산생물학 | - |
dc.subject | 생물정보 학 | - |
dc.subject | 전사체 | - |
dc.subject | RNA-결합 단백질 | - |
dc.subject.ddc | 570 | - |
dc.title | Comprehensive understanding of the determinants for functional microRNA targeting | - |
dc.title.alternative | 마이크로RNA의 기능적인 표적 조절 인자의 포괄적인 이해 | - |
dc.type | Thesis | - |
dc.type | Dissertation | - |
dc.contributor.AlternativeAuthor | Doyeon Kim | - |
dc.contributor.department | 자연과학대학 생명과학부 | - |
dc.description.degree | Doctor | - |
dc.date.awarded | 2021-02 | - |
dc.identifier.uci | I804:11032-000000164000 | - |
dc.identifier.holdings | 000000000044▲000000000050▲000000164000▲ | - |
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