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研究生:蘇育揚
研究生(外文):Yu-Yong Su
論文名稱:研究線蟲中異質核醣核蛋白MSI-1以及HRP-2在let-7抑制lin-41的路徑中扮演的角色
論文名稱(外文):To investigate the roles of C. elegans hnRNPs MSI-1 andHRP-2 in let-7-mediated lin-41 repression
指導教授:詹世鵬
指導教授(外文):Shih-Peng Chan
口試日期:2017-07-14
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:154
中文關鍵詞:微型核醣核酸let-7異質核醣核蛋白
外文關鍵詞:miRNALET-7hnRNP
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異質核醣核蛋白是已知會參與在RNA生合成的各個步驟中,包括轉錄、RNA剪接、運輸、轉譯、降解。在過去十年中,異質核醣核蛋白被發現會調節某些微小核糖核酸(miRNAs)的生合成或功能。微小核醣核酸是一群長度小且不會轉譯成蛋白質的功能型RNA,會透過後轉錄階段結合在目標基因的3′UTRs上並引發轉譯之抑制以及mRNA之降解。其中,let-7為最早被發現的miRNA成員中的一員,會在幼蟲進入成蟲階段時透過抑制lin-41調控細胞增生以及細胞的最終分化。LIN-41蛋白會抑制成蟲轉錄因子lin-29的表現,所以當lin-41失能突變後會顯著地造成早熟性狀,而let-7發生失能變異時會無法抑制lin-41使lin-29延後表現,而引發發育遲緩。不管在人類或是線蟲都有發現let-7抑制lin-41的現象,顯示這是一個具有演化保守性的發育基因調節機制,而且let-7功能的缺失目前被發現與不同癌症有相關。
在本篇論文中,我們利用RNAi篩選線蟲中會影響let-7生合成或功能的異質核醣核蛋白,我們發現減少MSI-1的表現後會抑制溫度敏感let-7部分失能變異所造成的表現型,包括seam cells的終端分裂延後以及生殖孔的發育不全,而在lin-29移除的線蟲中就無法觀察到減少MSI-1表現抑制發育遲緩的現象。此外,我們利用lin-29::mCherry做為報導蛋白發現,降低msi-1表現似乎能夠使lin-29提早在L3階段表現。接著我們使用GFP做為報導基因,後方在接上lin-41 3′UTR、lin-41移除let-7結合位或是接上已知不會與let-7有作用的unc-54 3′UTR,實驗結果顯示當我們降低msi-1後會影響let-7抑制lin-41的能力。根據以上的結果,我們猜測msi-1在let-7抑制lin-41的路徑中扮演著一個負向調控的角色。有趣的是,我們北方墨點法的結果顯示減少msi-1的表現不會影響到let-7的表現,也支持了MSI-1會影響let-7的功能而非表現量,可能在lin-41 3′UTR上有MSI-1的結合位降低let-7的結合或是可以抵擋let-7對lin-41轉譯的抑制,未來我們的研究想了解MSI-1與lin-41 mRNA之間的分子機制。
Heterogeneous nuclear ribonucleoproteins (hnRNPs) have been demonstrated to participate in almost all RNA metabolisms, including transcription, splcing, RNA transport, translation and RNA degradation. In the past decade, hnRNPs were also found in regulation of biogenesis and/or function for certain microRNAs (miRNAs). miRNAs are a group of small noncoding regulatory RNAs that inhibit gene expression at the post-transcriptional level via binding to the 3′UTRs of target mRNAs and triggering translational repression and mRNA degradation. Among them, let-7, one of the founding members, regulates cell proliferation and terminal differentiation in Caenorhabditis elegans majorly by inhibiting the heterochronic gene lin-41 at the larva-to-adult transition of the nematode. The LIN-41 protein represses expression of the adult-specific transcription factor lin-29, hence loss-of-function mutations in lin-41 strongly exhibit precocious phentotypes and let-7 loss-of-function usually results in retardation due to the inability to inhibt lin-41. The let-7-mediated repression on lin-41 has been demonstarted to be evolutionarily conserved from the nematodes to humans and malfunction of let-7 frequently is associated with a variety of cancers. Here, we preform RNAi screen in the nematode C. elegans to seek hnRNPs that are required for biogenesis and/or function of the let-7 miRNA. We found that depletion of MSI-1 by RNAi suppressed the retarded phenotypes caused by the hypomorphic temperature-sensitive let-7(n2853) mutation, such as delayed terminal differentiation of seam cells and the defects in vulval development, but not the retardation of the lin-29(n333) null mutant. In addition, msi-1 knockdown seemed to induce precocious expression of lin-29, monitored by observation on a lin-29::mCherry reporter that should be expressed in seam cells initially from the L4 stage. Moreover, we utilized GFP reporters fused with the lin-41 3′UTR, lin-41 3′UTRΔLCS (LCS stands for let-7 complementary sequences) or the 3′UTR of unc-54, which is not regulated by let-7, to determine whether depletion of MSI-I indeed affects let-7 regulation on lin-41 and saw a positive relevance. Thus, we propose that MSI-1 acts as a negative regulatory factor for let-7 to repress lin-41 in the let-7-lin-41-lin-29 axis. Interestingly, our results in northern blotting assays showed no changes in the let-7 level upon msi-1 knockdown, suggesting that MSI-1 may acts on let-7 functioning but not biogenesis, perhaps recognizing target sequences in the lin-41 3′UTR or repressing translation of the lin-41 mRNA. Further investigation is needed to determine the molecular mechanism underlying.
口試委員會審定書………………………………...…………………………..…. #
誌謝………………………………………………………………….…..………….. i
中文摘要……………………………………………………….………..…………. ii
英文摘要………………………………...………………………………………… iv
目錄……………………………………………………………………………..... vi
第一章 引言…………………………………………………………………… 1
1.1 微型核醣核酸miRNAs……………………………………………….... 1
1.2 let-7………………………………………………………………………. 3
1.3 異質核醣核蛋白hnRNP…………..………………………………….... 5
第二章 實驗材料…...…………………………………………………………. 7
2.1 菌種品系……………………………………………................................ 7
2.1.1 OP50……………..………..…………………………………...…. 7
2.1.2 HT115……………………..…………………………………...…. 7
2.1.3 DH5α……………………..…………………………………....…. 7
2.2 線蟲品系……………………………………………................................ 7
2.3 PCR引子…….……………………………………………….................... 9
2.3.1 RNAi質體構築………..……………………………………………. 9
2.3.2 線蟲genotyping引子………..…….....…………………………. 10
2.3.3 CRISPR引子………..……..…….…………………………….…. 11
2.4 培養液…………………………………………………….................... 13
2.4.1 LB培養液………..………..…………………………………...…. 13
2.4.2 M9緩衝液………..………..…………………………………...…. 13
2.4.3 NGM培養基………..……..…………………………………..…. 13
2.4.4 IPTG培養基………..………..………………………………...…. 13
第三章 實驗方法…...…………………………………………………………. 14
3.1 線蟲生長同步化………………………………………….................... 14
3.2 核醣核酸干擾作………………………………………….................... 14
3.3 聚合酶鏈鎖反應………………………………………….................... 15
3.4 北方墨點法………………………………………………….................. 16
3.4.1 線蟲RNA萃取……..……….…..………………………..…...…. 16
3.4.2 北方墨點法流程……..……..………………………………...…. 17
3.4.3 RNA探針製備……....……..……………………………..…...…. 18
3.4.4 探針引子序列……....………..…………………………….....…. 19
3.5 RT-PCR, qRT-PCT………………………………………....................... 19
3.5.1 RNA tailing……..……….…….…………………………..…...…. 19
3.5.2 Reverse transcription……..…………….…..…………………...…. 20
3.5.3 DNase treatment……..……….….……………………………...…. 20
3.5.4 cDNA synthesis……..……….….……………………………...…. 21
3.5.5 RNase A/H treatment……………….…..……………………...…. 21
3.5.6 qPCR……..……….…..………………..……………………...…. 22
3.5.7 primer secquence……..……….………………………….…...…. 22
3.6 線蟲玻片製作……………………………………………….................. 23
第四章 實驗結果……………………………………………..……….………. 24
4.1 降低線蟲中msi-1或是C44B7.2可以抑制let-7突變所造成的表現型………………………………………………………………………….... 24
4.2 降低線蟲中msi-1或是C44B7.2無法改變lin-29剔除所造成的表現
型……………………………………………………………..……………... 26
4.3 降低線蟲中msi-1或是C44B7.2可以使其lin-29提早表現….......... 27
4.4 降低線蟲中msi-1可以使L4階段的線蟲中lin-41的表現減少…...…. 28
4.5 降低線蟲中msi-1或是C44B7.2並不會影響到線蟲體內let-7的表現
量……………………………………………………………………………... 29
第五章 討論………...……………………………………………..………..…. 30
第六章 圖表………...…………………………………………………………. 32
第七章 參考文獻………...……………………………………………………. 48
附錄 ……………………………………………………….…………..……. 53
附錄一 最初鎖定之hnRNP表格………….…………………..................... 53
附錄二 let-7(n2853)第一次Seam cells觀察紀錄表 n=10.......................... 54
附錄三 let-7(n2853)第二次Seam cells觀察紀錄表 n=10.......................... 54
附錄四 let-7(n2853)第三次Seam cells觀察紀錄表 ……........................... 55
附錄五 let-7(n2853) Seam cells統計計算表………….………..….......... 58
附錄六 lin-29(n333) 第一次Seam cells觀察紀錄表 n=10……..…......... 58
附錄七 lin-29(n333) 第二次Seam cells觀察紀錄表 n=10………........... 59
附錄八 lin-29(n333) 第三次Seam cells觀察紀錄表 …….………........... 60
附錄九 lin-29(n333) Seam cells統計計算表…………………..…….......... 62
附錄十 第一次lin-29::mCherry觀察紀錄表 n=10……….………….…... 63
附錄十一 第二次lin-29::mCherry觀察紀錄表 n=10……….….………... 63
附錄十二 第三次lin-29::mCherry觀察紀錄表 n=10……….……….…... 64
附錄十三 lin-29::mCherry總統計表………….……………....................... 65
附錄十四 pwrt-2::GFP::lin-41 3′UTR第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)………………………………...….………............. 65
附錄十五 pwrt-2::GFP::lin-41 3′UTR第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)………………………..……...….…………........... 68
附錄十六 pwrt-2::GFP::lin-41 3′UTR第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)………………………………...….……..…........... 74

附錄十七 pwrt-2::GFP::lin-41 3′UTR第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)………………………………...….……..…........... 80
附錄十八 pwrt-2::GFP::lin-41 3′UTR第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)………………………………...….……...….......... 86
附錄十九 pwrt-2::GFP::lin-41 3′UTR第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)……………………………….....….………........... 92
附錄二十 pwrt-2::GFP::lin-41 3′UTRΔLCS第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)………………………………..…..…........... 98
附錄二十一 pwrt-2::GFP::lin-41 3′UTRΔLCS第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)…………………...………………........... 100
附錄二十二 pwrt-2::GFP::lin-41 3′UTRΔLCS第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)…………………...………………........... 106
附錄二十三 pwrt-2::GFP::lin-41 3′UTRΔLCS第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...………………........... 112
附錄二十四 pwrt-2::GFP::lin-41 3′UTRΔLCS第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...………………........... 114
附錄二十五 pwrt-2::GFP::lin-41 3′UTRΔLCS第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...………………........... 120

附錄二十六 pwrt-2::GFP::unc-54 3′UTR第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)…………………...……………….................... 126
附錄二十七 pwrt-2::GFP::unc-54 3′UTR第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)…………………...……………….................... 128
附錄二十八 pwrt-2::GFP::unc-54 3′UTR第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L2 stage)……………….………...………………........... 134
附錄二十九 pwrt-2::GFP::unc-54 3′UTR第一次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...……………………........... 140
附錄三十 pwrt-2::GFP::unc-54 3′UTR第二次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...…………….…………........... 142
附錄三十一 pwrt-2::GFP::unc-54 3′UTR第三次細胞定量,一隻線蟲圈選10顆細胞進行定量(L4 stage)…………………...…………….…………....... 148
附錄三十二 Northern blot 第一次結果定量數值……….…….……....... 154
附錄三十三 Northern blot 第二次結果定量數值……….…….……....... 154
附錄三十四 Northern blot 第三次結果定量數值……….…….……....... 154
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