系統識別號 U0026-1912201722390500
論文名稱(中文) 人類造精功能低下症之MAEL基因甲基化異常
論文名稱(英文) Methylation dysregulation of MAEL gene in human hypospermatogenesis
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 106
學期 1
出版年 106
研究生(中文) 鄭裕生
研究生(英文) Yu-Sheng Cheng
學號 S98971021
學位類別 博士
語文別 英文
論文頁數 121頁
口試委員 指導教授-林永明
中文關鍵字 非阻塞性無精子症  造精功能低下症  MAEL  LINE-1  甲基化 
英文關鍵字 non-obstructive azoospermia  hypospermatogenesis  MAEL  LINE-1  methylation 
中文摘要 非阻塞性無精症(NOA)是男性不孕症的一項挑戰。人類造精功能低下症(HS)則是非阻塞性無精症中最常見的病理組織學上的表現。為了深入了解這一個疾病,我們初步報導了100例NOA和HS患者的臨床特徵和後續取精結果。這是目前為止該疾病發表最多個案數的研究。我們發現嚴重HS主要是由基因遺傳異常引起,而輕度HS較可能是由於後天性睾丸受損因素造成。高達55%的NOA與HS的發生原因不明,值得進一步的研究。目前已知啟動子的高度甲基化會降低基因的表現。為了揭示NOA與HS是否導因於生殖相關基因上高甲基化可能的角色,我們採用了全基因組甲基化分析和人類睾丸微陣列mRNA分析,找出甲基化異常的候選基因。經過進一步驗證,BOLL,DDX4,HORMAD1和MAEL這四個基因可能在人類精子發生的表遺傳調控中發揮重要作用。
我對MAEL基因甚感興趣,因為它已被證明在哺乳動物中可透過piRNA介導來防禦逆轉錄轉座子對基因序列的攻擊。雄性MAEL基因剔除鼠表現是不孕合併減數分裂停滯。我們特別標定出了位於第一染色體上的166958215〜166958522位置含有26個CpG位點,這些CpG位點對於MAEL的基因調控可能是非常重要的。為了闡明MAEL啟動子上甲基化對MAEL基因和轉座因子LINE-1基因表現量的影響,我們研究了此段MAEL啟動子區域的啟動子活性,並在人類H358細胞株中成功的建立了目標DNA甲基化(TDM)報導系統。結果顯示: MAEL啟動子的目標DNA甲基化會抑制MAEL基因的表現量,但卻增加了LINE-1基因的表現量。 TDM是研究特定啟動子區域上甲基化調控的有用工具。為了確定人類睾丸中MAEL基因的甲基化程度高低,並探討MAEL甲基化與臨床特徵的關係,我們通過焦磷酸測序技術驗證了這26個CpG位點的甲基化狀態,並確定了這26個CpG位點的甲基化狀態與病人睪丸內MAEL基因表現量和LINE1基因表現量的相關性。 人類造精功能低下症(HS)患者的MAEL啟動子中這26個連續的CpG位點的平均甲基化程度明顯高於正常造精功能的人(NS)。 MAEL啟動子上的甲基化程度與MAEL基因轉錄程度兩者呈負相關,MAEL甲基化程度升高與嚴重的造精功能障礙有關。 HS患者睪丸內的LINE-1基因表現量顯著升高。 而MAEL啟動子上甲基化水平高或低和患者年齡,睾丸損害頻率和遺傳異常上沒有差異。
英文摘要 Non-obstructive azoospermia (NOA) is one of the challenges in male infertility. Hypospermatogenesis (HS) serves the most common histopathology of NOA. To understand this disease entity, we initially reported the clinical features and sperm retrieval outcomes of 100 patients with NOA and HS, which is the largest series published to date. We found severe HS was caused mostly by genetic anomalies, and mild HS was more likely caused by acquired testicular insults. We reported that 55% of NOA with HS is with the idiopathic origin and deserve further investigation. The hypermethylation of promoter is known to silence gene expression. To uncover the role of aberrant methylation of reproduction-related genes in NOA with HS, the genome-wide methylation profiling and mRNA microarray of human testes were analyzed to search the candidate genes. After validation, BOLL, DDX4, HORMAD1, and MAEL may play crucial roles in epigenetic regulation of human spermatogenesis.
I am interested in MAEL gene because it has been shown to play a major role in the piRNA-mediated defense of the mammalian germ line from retrotransposons and male MAEL null mice are sterile due to meiotic arrest. We specifically identified 26 CpGs located on chromosome one: 166958215~166958522 which may be crucial for the regulating targets of MAEL. To clarify the effects of the MAEL promoter methylation on the expressions of MAEL and transposable elements LINE-1, we investigated the promoter activity of the predicted MAEL region and established target DNA methylation(TDM) reporter system in human H358 cells. The results showed the targeted DNA methylation of MAEL promoter suppressed MAEL expression and de-repressed LINE-1 activity in vitro. TDM is a useful system to study the methylation regulation of predicted promoter region. To determine the methylation levels of MAEL gene in human testes, and to explore the associations of MAEL methylation with clinical features, we verified the methylation status of these 26 CpG sites by pyrosequencing technology and determined the correlation to MAEL expression profile and LINE1 expression. HS patients had significantly higher mean methylation levels of 26 consecutive CpGs in the MAEL promoter, compared to patients with normal spermatogenesis. The MAEL methylation levels were negatively correlated with MAEL transcript levels and higher methylation level of MAEL was associated with the severe spermatogenic defect. LINE-1 transcript level significantly increased in patients with HS. No differences in age, the frequency of testicular insults and genetic anomalies were noted between patients with high or low MAEL methylation levels.
In conclusion, dysregulated methylation of MAEL promoter may lead to de-repression of LINE-1, which may contribute to one of the causes of spermatogenic failure in infertile men. Understanding the methylation dysregulation of MAEL promoter may advance our knowledge of the complex mechanism of human spermatogenic failure and form the basis for the future breakthrough in clinical practice for male infertility.
論文目次 Chapter 1 Introduction 1
1.1 Non-obstructive azoospermia(NOA) in male infertility 1
1.2 Histopathology of hypospermatogenesis(HS) in NOA 4
1.3 Known genetic causes in male infertility 5
1.4 known epigenetic roles in spermatogenesis 7
1.5 Thesis Aim 10
Chapter 2 Clinical Features of 100 Infertile Men With NOA and HS in NCKUH ...........................................................................................11
2.1 Backgrounds and Aims 11
2.2 Materials and Methods 12
2.2.1 Selecting NOA patients with HS 12
2.2.2 Intensive chart reviewing for history taking, physical examination, and laboratory workup 13
2.2.3 Testicular biopsy and spermatogenic score 14
2.2.4 Testicular sperm extraction 15
2.2.5 Statistical analysis 16
2.3 Results 16
2.3.1 Clinical features of patients with NOA and HS 16
2.3.2 Comparing the clinical features of patients with NOA and HS based on their spermatogenic score 17
2.4 Discussion 19
2.5 Figures and Tables 22
Chapter 3 Aberrant Methylation of BOLL, DDX4, HORMAD1,and MAEL Promoter is Associated with HS and NOA after High Throughput Analysis 27
3.1 Backgrounds and Aims 27
3.2 Materials and Methods 29
3.2.1 Genome-wide methylation profiling and microarray mRNA expression analysis of human testes 29
3.2.2 Identification of candidate gene by bioinformatics analysis 31
3.2.3 Validation of candidate genes by quantitative real-time RT-PCR and pyrosequencing analysis 31
3.2.4 Statistical analysis 32
3.3 Results 33
3.3.1 Differential DNA methylation and mRNA expression in testes from HS versus NR 33
3.3.2 Validation of mRNA and DNA methylation levels 34
3.4 Discussion 34
3.5 Figures and Tables 39
Chapter 4 The Hypermethylated MAEL Promoter(-188 to +294) can De-repressed LINE-1 Activity in Human NCI-H358 cells 46
4.1 Backgrounds and Aims 46
4.2 Materials and Methods 48
4.2.1 Selecting human cell line investigate methylation of MAEL promoter 48
4.2.2 Promoter construct 48
4.2.3 In vitro DNA methylation and luciferase assay 49
4.2.4 Establishing targeted DNA methylation system (TDM) of MAEL promoter 50
4.2.5 Statistical analysis 53
4.3 Results 54
4.3.1 Identification of regulatory region of MAEL gene 54
4.3.2 Targeted DNA methylation of MAEL promoter suppresses MAEL expression and de-represses LINE1 activity in vitro 55
4.4 Discussion 56
4.5 Figures and Tables 59
Chapter 5 Dysregulated Methylation of 26 CpGs in MAEL Promoter (-131 to +177) is Associated with HS in Infertile Men 72
5.1 Backgrounds and Aims 72
5.2 Materials and Methods 74
5.2.1 Patients grouping and testicular samples 74
5.2.2 DNA extraction and bisulphite DNA modification 75
5.2.3 Promoter methylation analysis by pyrosequencing technology 75
5.2.4 Statistical analysis 76
5.3 Results 76
5.3.1 Differential methylation patterns of the MAEL promoter in patients with HS versus NS 76
5.3.2 The associations of MAEL methylation levels with gene expression and testicular phenotype 77
5.3.3 Comparing the clinical features of patients based on methylation levels 78
5.4 Discussion 79
5.5 Figures and Tables 83
Chapter 6 General Discussion, Conclusion and Prospectives 98
6.1 Experimental findings 98
6.2 Methodological considerations 100
6.3 Prospectives 101
Bibliography 104
Publication List 116

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