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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹世鵬(Shih-Peng Chan) | |
| dc.contributor.author | Yen-Ting Hsu | en |
| dc.contributor.author | 徐晏婷 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:31:17Z | - |
| dc.date.available | 2020-09-25 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-30 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53848 | - |
| dc.description.abstract | 微小核醣核酸(MicroRNAs or miRNAs)是一段約22個核苷酸長的non-coding RNA，主要是透過結合在目標基因的3端不轉譯區，抑制其轉譯或是造成mRNA降解來調控基因的表現。 在線蟲中，let-7 微小核醣核酸透過降低lin-41的表現調控線蟲從第四幼蟲期到成蟲的轉換。低量的 let-7 表現無法有效抑制lin-41，會造成線蟲上皮接縫細胞 (hypodermal seam cell) 終端分化遲緩及外陰發育不正常。表現let-7亞效等位基因的線蟲 (n2853) 通常會在幼蟲轉換至成蟲時，產生接縫細胞最終分化延遲以及外陰爆裂死亡的性狀。let-7 miRNA調控lin-41表現的現象在物種間具有保守性。在人類中，let-7低量表現或其調控的目標基因如LIN41/TRIM71及LIN28等致癌基因，則與許多癌症的發生有高度相關性。為了進一步釐清miRNA調控的機制，尤其是let-7對於lin-41的調控，我們試圖去找出可能參與let-7生合成或功能的DEAD-box 核醣核酸解旋酶蛋白，及異質核醣核酸蛋白Heterogeneous ribonucleoproteins (hnRNPs)。透過在線蟲內進行RNA干擾篩選實驗，我們發現降低核醣核酸解旋酶DDX-47以及異質核醣核酸蛋白HRP-2的表現，可以抑制let-7亞效等位基因線蟲 let-7(n2853) 異時基因異常的性狀，顯示此兩種蛋白可能與let-7的功能有關。在此，我們證實 DDX-47 影響核醣體核醣核酸的生合成，降低DDX-47表現導致核醣體壓力，可能引發其他非 let-7 調控路徑表現去抑制 let-7(n2853)突變株的性狀。另一方面，我們證實HRP-2可以與lin-41 之3端不轉譯區上一段腺嘌呤-尿嘧啶豐富序列結合。有趣的是，人類中HRP-2的同源蛋-hnRNP Q也會與TRIM71/LIN41的3端不轉譯區上腺嘌呤豐富序列有交互作用。去除掉hnRNP Q的結合位可以提高let-7抑制的現象，根據結果顯示出此具有物種間保守性的hnRNP可能透過介入miRNA和3’UTR間的交互作用來調控lin-41表現。 | zh_TW |
| dc.description.abstract | MicroRNAs (miRNAs) are ~22-nt-long small non-coding that usually regulate gene expression by binding to the 3’UTRs of target mRNAs and triggering translational repression and/or mRNA degradation. In C. elegans, the let-7 miRNA down regulates lin-41 that controls transition from the 4th larva stage to adults. Low levels of let-7 cause inefficient repression of lin-41, leading to attenuated terminal differentiation of hypodermal seam cells and abnormal vulval morphorgenesis. Animals carrying a hypomorphic let-7(n2853) allele exhibit reiterated division of seam cells and die by bursting through the vulva. The regulation of lin-41 by let-7 is conserved across species. In humans, serveral let-7 targets, including LIN41/TRIM71 and LIN28, are oncogenic and low expression of let-7 has been shown highly correlated to a variety of cancers. To better understand miRNA-mediated regulation, the regulation of lin-41 by let-7 in particular, we sought to identify novel effecting factors from the DEAD-box RNA helicase family and heterogeneous nuclear ribonucleoproteins (hnRNPs) for let-7 biogenesis and/or function. By candidate-based RNAi screens in C. elegans, we have found that depletion of the RNA helicase DDX-47 or the hnRNP HRP-2 suppressed the heterochronic phenotypes caused by let-7(n2853), suggesting that these proteins may function with let-7. Here, we show that DDX-47 affects ribosomal RNA biogenesis and may suppress the let-7 heterochronic phenotypes through a parallel pathway, perhaps induced by nucleolar stress. HRP-2 binds to an AU-rich element of the lin-41 3’UTR. Interestingly, the human HRP-2 homolog, hnRNP Q, also interacts with the TRIM71/LIN41 3’ UTR through binding to an A-rich region. Deletion of this putative hnRNP Q binding site enhances repression by let-7, suggesting a role of this conserved hnRNP in the regulation of lin-41 through miRNA-3’UTR interaction. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:31:17Z (GMT). No. of bitstreams: 1 ntu-104-R02445134-1.pdf: 5098013 bytes, checksum: 251f2913c03bd73aaf01839a619b0db9 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書 # 誌謝……………………………………………………………………1 中文摘要…………………………………………………………………2 ABSTRACT 3 CONTENTS 4 Chapter 1 Introduction 9 1.1 miRNAs 生合成與基因調控 9 1.2 let-7 與線蟲發育的關係 10 1.3 DEAD-box核醣核酸解旋酶(DEAD box RNA helicases) 11 1.3.1 參與miRNAs生合成或作用相關的DEAD-box核醣核酸解旋酶 11 1.3.2 篩選出與let-7生合成或作用相關的DEAD-box核醣核酸解旋酶 12 1.4 異質核醣核酸蛋白(heterogenous nuclear ribonuclearproteins, hnRNPs) 13 1.5 鑑別出HRP-2/hnRNP Q可能參與let-7 作用之功能上 14 1.6 實驗動機 16 Chapter 2 Materials and Methods 18 2.1 線蟲品系(strains) 18 2.2 固態培養基培養法 18 2.2.1 線蟲生長同步化 18 2.2.2 收取L4線蟲 18 2.3 RNA Interference (RNAi) 19 2.3.1 RNAi clone的製備 19 2.3.2 Feeding RNAi 19 2.4 線蟲細胞萃取液製備 19 2.5 西方墨點法 20 2.5.1 PAGE膠體製備 20 2.5.2 樣品配製與膠體電泳 20 2.6 線蟲RNA萃取 21 2.7 北方墨點法 21 2.7.1 聚丙烯胺膠體電泳 21 2.7.2 探針製備 21 2.7.3 瓊脂糖-甲醛膠體電泳 22 2.8 Biotin-Streptavidin Affinity Pull Down Assay 24 2.8.1 in vitro transcription with biotin-labeled UTP 24 2.8.2 RNA 膠體純化 25 2.8.3 RNA pull down 25 2.9 細胞培養 26 2.9.1轉染(Transfection) 26 2.10 免疫共沉澱法 27 2.11 Random Priming qRT-PCR 27 2.11.1 rDNaseⅠdigestion 27 2.11.2 Reverse Transcription 28 2.11.3 qPCR 28 2.12 Luciferase Assay 29 Chapter 3 Results 30 3.1 DDX-47以負向調控的方式參與在let-7的異時調控路徑中 30 3.1.1 降低DDX-47表現可以抑制let-7(n2853)突變株無法正常表現成蟲基因COL-19的情形 30 3.1.2 降低DDX-47表現可有效抑制let-7(n2853)突變株中seam cell 終端分化異常的現象 30 3.2 降低DDX-47表現不影響let-7的生合成 31 3.3 降低DDX-47表現可能促進LIN-29 independent路徑的活化 31 3.3.1 降低DDX-47表現促進部分LIN-29 突變株中COL-19的表現 32 3.3.2 降低DDX-47表現抑制LIN-29 突變株中seam cell 終端分化異常的情形 32 3.4 降低DDX-47表現可能導致pre-rRNA processing缺失造成細胞核醣體壓力 33 3.5 降低DDX-47表現可能導致CEP-1的活化 33 3.6 鑑別HRP-2在lin-41 mRNA 3端非轉譯區結合位的專一性 34 3.7 鑑別hnRNP Q在TRIM71 mRNA 3端非轉譯區結合位的專一性 34 Chapter 4 Discussion 38 4.1 DDX-47與miRNA的關聯性 38 4.2 降低DDX-47造成18S ribosomal RNA缺失與調控LIN-29下游基因的關係不明 38 4.3 HRP-2 結合位在線蟲體內的生理意義以及分子機制 39 4.4 hnRNP Q結合位與let-7 miRISC交互作用的機制有待進一步探討 40 Chapter 5 Figures 41 Figure 1. 降低DDX-47可以抑制let-7 (n2853)突變株無法表現Collegen-19的情形 41 Figure 2.降低DDX-47可以抑制let-7 (n2853)突變株產生seam cell異常分裂的情形 42 Figure 3.降低DDX-47表現，不影響mature let-7的表現量 43 Figure 4.降低DDX-47可以抑制部分lin-29 突變株無法表現col-19以及異常的seam cell 數目的情形 45 Figure 5.降低DDX-47表現會造成rRNA processing的缺失 46 Figure 6.降低DDX-47表現會促使線蟲生殖腺內CEP-1表現量上升。 47 Figure 7. 同時降低DDX-47以及CEP-1仍可以促進 lin-29 突變株表現col-19 48 Figure 8. lin-41 mRNA 3端不轉譯區片段6-1-1有明顯HRP-2結合的情形 49 Figure 9.在人類Huh7 細胞中hnRNP Q與TRIM71 mRNA之間有交互作用 50 Figure 10.TRIM71 3端不轉譯區的片段6-6為hnRNP Q特異性結合序列 52 Figure 11.hnRNP Q特異性結合位對於細胞中let-7調控TRIM71 mRNA的重要性 53 Figure 12. HRP-2及hnRNP Q與其特異性結合位結合影響let-7 miRISC的調控功能 55 Chapter 6 References 56 Chapter 7 Appendix 59 附圖 一、線蟲heterochronic gene pathway 與seam cell 分化的關係 59 附圖 二、DEAD -box RNA 解旋酶結構 60 附圖 三、let-7 (n2853)內進行48個DEAD box RNA 解旋酶RNAi後線蟲的存活率 61 附圖 四、對線蟲let-7(n2853)已知的DEAD box RNA解旋酶進行RNAi 後seam cell 及hypodermal cell中 col-19::gfp表現之情形 62 附圖 五、組織染色確認DDX-47主要分布在核仁 63 附圖 六、線蟲內進行hrp-2(RNAi)鑑定出與HRP-2與let-7 功能有關 64 附圖 七、降低HRP-2表現會影響到LIN-41的表現 66 附圖 八、HRP-2與lin-41 mRNA有交互作用 67 附圖 九、線蟲lin-41 3’UTR上有HRP-2特異性結合位 68 附圖 十、人類細胞中hnRNP Q參與let-7 miRISC調控的功能 69 附圖 十一、線蟲lin-41 3’UTR 序列資料與PCR primer 位置示意圖 70 附圖 十二、人類TRIM71 3’UTR 序列資料與PCR primer 位置示意圖 71 附圖 十三、psiCHECK2_TRIM71 3’UTR質體建構之序列資料與流程 73 附圖 十四、pKH3_3HA_hnRNP Q1質體序列資料 74 附表一 let-7 (n2853) wIs51 seam cell 數目統計數據 (for Fig. 2C) 75 附表二 N2 N2853 ddx-47(RNAi)的let-7 northern blot 定量分析結果(For Fig.3B) 76 附表三lin-29 (n333) seam cell 數目統計數據 (for Fig. 4D) 77 附表四Dual Luciferase Assay原始統計數據 (for Fig.11B) 78 | |
| dc.language.iso | zh-TW | |
| dc.subject | 異質核醣核酸蛋白 | zh_TW |
| dc.subject | DEAD-box核醣核酸解旋? | zh_TW |
| dc.subject | 線蟲 | zh_TW |
| dc.subject | C. elegans | en |
| dc.subject | DEAD- box RNA helicase | en |
| dc.subject | heterogeneous ribonucleoprotein | en |
| dc.title | 線蟲DEAD-box核醣核酸解旋酶DDX-47及異質核醣核酸蛋白HRP-2/hnRNP Q在let-7 miRNA功能之角色 | zh_TW |
| dc.title | The roles of C. elegans DEAD-box RNA helicase DDX-47 and heterogeneous nuclear ribonucleoproteins HRP-2/hnRNP Q in let-7 microRNA function | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 朱家瑩(Chia-Ying Chu),賴銘志(Ming-Chih Lai) | |
| dc.subject.keyword | 線蟲,DEAD-box核醣核酸解旋?,異質核醣核酸蛋白, | zh_TW |
| dc.subject.keyword | C. elegans,DEAD- box RNA helicase,heterogeneous ribonucleoprotein, | en |
| dc.relation.page | 79 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-07-30 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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