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系統識別號 U0026-0812200914355054
論文名稱(中文) 探討人類DAZL基因在後轉錄過程中的分子調控機制
論文名稱(英文) Characterization of post-transcriptional regulation mechanisms of DAZL gene
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 96
學期 2
出版年 97
研究生(中文) 邱詩方
研究生(英文) Shih-Fang Chiu
學號 T1695408
學位類別 碩士
語文別 英文
論文頁數 69頁
口試委員 指導教授-曾大千
指導教授-郭保麟
口試委員-孫孝芳
口試委員-譚婉玉
中文關鍵字 DAZL 基因  YB2蛋白  後轉錄調控機制  男性不孕症 
英文關鍵字 male infertility  post-transcriptional regulation  DAZL gene  YB2 
學科別分類
中文摘要 現今社會,不孕症是困擾年輕男女的常見疾病之一。全世界大約有15%的夫婦有不孕症的困擾,其中約有50%的不孕症是由男性因素直接或間接所導致的。大部分的男性不孕症被認為是由於在精子形成的過程中,參與分化的基因在調控機制上出了問題。最近有越來越多報導指出DAZL基因在始基生殖細胞的發育過程扮演重要角色,以及參與在生殖細胞的成熟與分化的過程中。目前,大部分的研究多著重在DAZL蛋白對於其他基因的調控機制,卻很少有研究報導DAZL基因是如何被調控的。除此之外,3’端非轉譯區域被認為在細胞分化及發育過程中,對於調控RNA的穩定性、分佈位置以及轉譯能力上,扮演重要的角色。因此,在本篇研究中,我們希望找出順式調控序列以及反式調控因子,用以闡明DAZL基因在後轉錄過程中可能的調控機制為何。在本實驗中,我們利用大鼠當作動物模式來找出參與在DAZL基因後轉錄過程中的可能要素有哪些:首先我們先將大鼠的Dazl3’端非轉譯區域分成不同片段並進行RNA-EMSA與UV-cross linking assay的實驗,試圖找出哪些蛋白質會和大鼠的Dazl3’端非轉譯區域結合;結果我們發現有些蛋白質會與大鼠的Dazl3’端非轉譯區域中的第1407個核苷酸到第1457個核苷酸作結合(簡稱為R4-1a區域)。接著,我們期望找出會跟R4-1a區域結合的蛋白:我們利用biotin pull down assay以及質譜儀的分析找出可能的反式調控因子為YB2,它是一個只會表現在睪丸組織的蛋白質,並且被認為與調控RNA的穩定度以及轉譯能力相關。接下來,我們利用生物資訊的工具在人類的DAZL3’端非轉譯區域找出與R4-1a最相似的區域並命名為H4-1a區域。接著,我們在台灣男性中找到有三個可能的變異點存在,其中在病人的DAZL3’端非轉譯區域,Del2601-2654出現的頻率對於控制組而言有顯著的增加,因此我們認為Del2601-2654可能與人類造精功能缺失有關;值得注意的是:Del2601-2654正巧與H4-1a區域吻合,因此大大提升我們想要探討H4-1a區域在DAZL基因的後轉錄調控機制為何。在冷光報導分析系統中,我們發現:無論是人類的H4-1a區域或是大鼠的R4-1a區域,皆對於調控DAZL基因的轉譯能力方面扮演關鍵的角色;換言之,DAZL基因3’端非轉譯區域一旦喪失該段區域,會使得DAZL的轉譯能力下降,這也暗示著病人所出現的Del2601-2654可能是由於H4-1a的喪失導致DAZL蛋白表現的下降因而出現造精功能缺失。此外,我們也發現一旦YB2結合到H4-1a區域的時候,會使得DAZL的mRNA穩定度提升,但使得轉譯能力下降;這也暗示我們:病人所出現的Del2601-2654有可能是由於YB2無法與H4-1a區域結合,進一步對DAZL作調控,因而出現造精功能缺失。總而言之,在本篇研究中我們發現,H4-1a區域以及YB2可能在DAZL基因的後轉錄過程的調控機制中扮演重要角色
英文摘要 Nowadays, infertility is one of the commonest diseases to afflict young men and women. Over the world, approximately 15% of couples suffered from infertility in which male factors occur in roughly half of these couples. Most cases with male infertility are caused by spermatogenic defect, which may refer to the mis-regulation of gene expression during spermatogenesis. Recently, there is increasing evidence for the critical roles of DAZL in the development of primordial germ cells and in germ cell differentiation and maturation. Genetic analysis and gene disruption studies have demonstrated that DAZL proteins play important roles in gametogenesis. But how DAZL is regulated still remained to be puzzle. In general, the regulation of mRNA stability, localization and translational efficiency are important through 3’untranlated region (UTR) in the processes of cellular differentiation and development. To decipher post-transcriptional regulation mechanisms of DAZL, we seek to identify cis-acting regulatory elements and trans-acting factors of DAZL. First, we utilized rat Dazl 3’UTR as animal model for identification of components involved in post-transcription regulation of DAZL gene. First of all, we divided rat Dazl 3’UTR into different parts for RNA-EMSA, followed by UV-cross link assay to surmise what kind of protein complex might be associated with rat Dazl 3’UTR. We found some proteins might bind with the sequence of rat Dazl 3’UTR from 1407bp to 1457bp which is named by the R4-1a region. After performing by biotin pull down assay and mass spectrometer, we identified a candidate trans-acting binding proteins, Y-box-binding protein 2 (YB2). YB2 is exclusively expressed in the testis and involved in the regulation of the stability and/or translation of germ cell mRNAs. After identifying rat Dazl 3’UTR specific binding factors, we identified the sequence from 2601bp to 2655bp of human DAZL 3’UTR is the most similar region (represented by H-4-1a) compared with the R4-1a region by bioinformatics tools. After that, we identified three variants within DAZL 3’UTR in Taiwanese and found the frequency of Del2601-2654 is more prevalent in patients than in controls that implied Del2601-2654 may be associated with human spermatogenic defect. Notably, Del2601-2654 is exactly matched to the H4-1a region. Therefore, we wondered to characterize the role of the H4-1a region. We found the translation efficiency of deletion of the H4-1a region of human DAZL 3’UTR is much lower than full length of human DAZL 3’UTR which harbored the same effect of rat the R4-1a region by luciferase reporter assay. It implied us H4-1a region is involved in translational regulation of DAZL gene. Next, we analyzed the effect of YB2 on post-transcriptional control of DAZL using luciferase reporter assay system, and found that binding of YB2 to the H4-1a region of DAZL 3’UTR elevate mRNA stability but repress translation efficiency of DAZL protein expression. In conclusion, we revealed the H4-1a region of DAZL 3’UTR and YB2 binding may play an important role in post-transcriptional regulation of DAZL gene which involved in human spermatogenic defect.
論文目次 TABLE OF CONTENTS
ABSTRACT IN CHINESE i
ABSTRACT IN ENGLISH iii
ACKNOWLEDGEMENT v
TABLE OF CONTENTS vii
LIST OF TABLES x
LIST OF FIGURES xi
1. INTRODUCTION 1
1.1 Definition and diagnosis of male infertility 1
1.2 Genetic causes of male infertility 1
1.3 The roles of DAZ gene family in spermatogenesis 4
1.4 The function of DAZL gene 6
1.5 The regulation of gene expression in Eukaryotes 7
1.5.1 The role of 5’UTR of in translational regulation 8
1.5.2 The role of 3’UTR in post-transcriptional regulation 9
1.7 Objective of this study 10
2. METERIALS AND METHODS 12
2.1 Total RNA isolation 12
2.1.1 From tissues 12
2.2.2 From cells 12
2.2 Reverse transcriptional polymerase chain reaction (RT-PCR) 13
2.3 Polymerase Chain Reaction (PCR) 13
2.4 Computational analysis 14
2.4.1 Restriction enzyme site prediction 14
2.4.2 Sequence alignment 14
2.5 Plasmid DNA preparation and DNA purification 14
2.5.1 Minipreparation of plasmid DNA 14
2.5.2 Midi-preparation of plasmid DNA 15
2.5.3 DNA Precipitation 16
2.5.4 Gel extraction 16
2.5.5 PCR clean-up 17
2.6 Generation of constructs 18
2.6.1 Construction of different fragments of rat Dazl 3’UTR 18
2.6.2 Construction of reporter plasmids with human DAZL 3’UTR and rat Dazl 3’UTR 19
Construction of pcDNA3.1/V5-His B- hYB2 plasmid 20
2.7 Total protein extraction 21
2.8 RNA electrophoretic mobility shift assay (RNA-EMSA) 21
2.8.1 In vitro transcription method 21
Electrophoresis 22
2.9 UV cross-linking 23
2.10 Biotin pull down assay 24
2.10.1 Western blot analysis 25
2.11 Silver staining 26
2.12 Cell culture 27
2.12.1 Routine maintain and subculture 27
2.12.2 Cell stock 27
2.13 Transient transfection and dual luciferase reporter assay 28
2.13.1 Transient transfection 28
2.13.2 Dual luciferase reporter assay 28
2.14 Real-time RT-PCR 29
3. RESULTS 31
3.1 Identification of cis-acting regulation element in the rat Dazl 3’UTR 31
3.2 Identification of trans-acting regulation factor in rat Dazl 3’UTR 32
3.3 Identification of cis-acting regulation element and trans-acting factor of human DAZL 3’UTR 33
3.4 Identify SNPs of DAZL 3’UTR in Taiwanese men 34
3.5 The effect of cis-acting regulation element of DAZL 3’UTR in post-transcription level 34
3.6 The effect of Y-box binding protein 2 in post-transcriptional level of human DAZL 3’UTR 36
4. DISCUSSIONS 38
4.1 H-4-1a region of human DAZL 3’UTR 38
4.2 The function of Y Box binding protein 2 during spermatogenesis 38
4.3 The possible post-transcriptional regulation mechanism of DAZL gene during spermatogenesis 41
References 42
TABLE 51
FIGURE 55
Appendix. 1 The similarity of YBX2 among different species. 68
CURRICULUM VITAE 69
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