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研究生:林聖傑
研究生(外文):Sheng-Chieh Lin
論文名稱:探討B型肝炎病毒表面抗原RNA調控之研究
論文名稱(外文):Study on the Regulation of Surface RNA in Hepatitis B Virus
指導教授:蘇宗笙
指導教授(外文):Tsung-Sheng Su
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
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:2008
畢業學年度:97
語文別:中文
論文頁數:93
中文關鍵詞:B形肝炎病毒剪接作用後轉錄調控因子
外文關鍵詞:HBVsplicing5' splice siteU1 snRNAEJCPREposttranscriptional regulatory element
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B型肝炎病毒(HBV)RNA上的後轉錄調控子(PRE)對於表面抗原RNA(surface RNA)的高度表現是必需的,研究發現PRE可以促進RNA從細胞核運送至細胞質中,藉此幫助surface RNA表現。而藉由pDM138報導基因系統模式對HBV的PRE進行功能上的分析,發現RNA二級結構SLα與SLβ1以及PTB結合位置對PRE的作用是重要的。除此之外,近來研究從病人純化出一突變HBV病毒株,在位於表面抗原ORF nt 458序列由G突變為A(G458A)會使HBV surface RNA在轉錄後的調控(posttranscriptional regulation)出現問題,而導致surface RNA表現下降。在HBV基因體上, nt 458位於一潛在剪接供位負1的位置,研究顯示G458A突變會抑制458-1305剪接RNA的產生。由以上發現突顯出一問題,即剪接作用與RNA運輸之間的平衡對surface RNA表現是重要的。
本研究以surface RNA表現系統驗證先前以pDM138報導基因系統發現對PRE功能有影響的cis-elements。發現當SLα結構被破壞時,會抑制surface RNA表現。然而破壞SLβ1或推測的PTB結合位置,對surface RNA表現卻無影響。值得注意的是,根據先前藉由HBV 3’逐段刪除的實驗定義PRE位置時,並未發現刪除含括此兩cis-elements的區域會影響PRE的功能。因此,得到不同結果可能是研究系統不同所造成。此外,以surface RNA表現質體進行實驗,本研究重現G458A突變會抑制surface RNA表現的發現。而在HBV surface RNA表現質體上插入rabbit β-globin的內隱子可以部份回復G458A突變所造成的影響,推測此剪接供位與RNA運輸之間有關聯。而當破壞surface RNA上所有已知的剪接受位,發現對surface RNA表現並無影響,推測假使剪接作用對surface RNA表現有影響的話,應該是在剪接作用早期剪接體形成時期。此外,藉由改變剪接供位序列,本研究發現剪接供位與U1 snRNA結合的穩定性會影響RNA的表現,對surface RNA表現而言,此穩定性比進行剪接作用來的重要。顯示剪接供位與U1 snRNA結合之步驟對HBV surface RNA表現是重要的。
The hepatitis B virus (HBV) posttranscriptional regulatory element (PRE) is a cis-sequence required for high level expression of viral surface transcripts and appears to function by promoting the export of the surface RNA from the nucleus. Functional studies of PRE have been heavily relied on the RNA export system pDM138. As a result, PRE sequences, such as RNA stem-loop �� (SL��), stem-loop ��1 (SL��1) and polypyrimidine tract binding protein (PTB) binding sites were found to be important for PRE function. On the other hand, recent report on the study of patients’ HBV isolates found a single G�莧 alteration within the surface gene at position 458 (G458A) acting at posttranscriptional level to reduce surface RNA expression. The nucleotide 458 is at �{1 position to a potential splice donor site SD459 on the HBV genome where G458A mutation was shown to prevent surface RNA splicing from position 458 to 1305. The finding raised an issue whether the delicate balance between splicing and export is essential in HBV surface RNA biogenesis.
In this study, we re-investigated the functional significance of PRE cis-elements defined by pDM138 reporter system under the nature context of HBV surface gene. We found that the surface RNA level decreased when the structure of SL�� was disrupted and otherwise not affected when SL��1 or putative PTB sites were mutated. It is noted that PRE was initially defined by serial truncations of the 3’ end of the HBV genome where no functional PRE sequences were found to locate in regions SL��1 or putative PTB binding sites mapped. Thus, the discrepancy of our findings to the previous arose by the systems chosen. We also reproduced and confirmed the effect of G458A mutation on surface RNA production in expression system employed in this study. Moreover, we found that surface RNA expression could be partially restored when a heterologous intron from the rabbit ��-globin gene was included into surface expression construct carrying G458A mutation, suggesting the function of splice donor site SD459 involves in surface RNA export. We also showed that the action of RNA splicing was rested at the early stage of spliceosome formation since elimination of all known splice acceptor sites on the surface RNA had no effect on its production. Furthermore, analysis of the effect of the splice donor site sequence on surface RNA expression indicates that the stability of splice donor site sequence bonds to U1 snRNA is more important than whether such site is functional in splicing. The results of this study show that the step of U1 snRNA binding to splice donor site SD459 is instrumental in HBV surface RNA biogenesis.
中文摘要............................................................................................................I
英文摘要...........................................................................................................II
壹、 緒論..........................................................................................................................1
A. B型肝炎病毒(Hepatitis B Virus).......................................................................1
B. 剪接作用(Splicing).............................................................................................2
C. 核醣核酸之運送(RNA export)...........................................................................3
D. B型肝炎病毒之RNA外送機制............................................................................4
E. RNA成熟過程中的相互連結................................................................................5
F. 研究目的與方向.....................................................................................................6
貳、 材料與方法...........................................................................................................8
A. 勝任細胞(Competent cell)製備.........................................................................8
B. 轉型作用(Transformation).................................................................................8
C. 小量質體DNA抽取(Mini-preparation of plasmid DNA)................................8
D. 大量質體DNA的抽取(Large-scale preparation of plasmid DNA)..................9
E. DNA/RNA濃度測定...............................................................................................9
F. ABI 3730自動核酸序列分析(Autosequence)..................................................10
G. 質體建構(Plasmid construction)........................................................................10
H. 寡核酸定點突變法(Site-directed mutagenesis)...............................................11
I. 細胞株及其培養(Cell culture).........................................................................12
J. 細胞株轉染(Transfection)................................................................................12
K. 細胞株全量RNA抽取(Isolation of total RNA).............................................12
L. 北方墨點法(Northern blot analysis)......................................................13
M. S1核酸酶定位法(S1 nuclease mapping analysis).............................................14
N. 反轉錄聚合酶鏈鎖反應(RT-PCR)...................................................................15
O. 本論文研究所用質體.................................................................16
參. 結果............................................................................................................................27
A. 後轉錄調控子(PRE)對HBV基因表現的影響...................................................27
a. 修飾表面抗原表現質體及共轉染之校正質體實驗模式.............................27
b. PRE上RNA的二級結構改變所造成的影響..............................................28
c. PRE上的推測蛋白結合序列突變對表面抗原表現的影響........................28
B. 大量表現spliceosome complex或RNA export相關蛋白質對HBV表面
抗原表現的影響..................................................................................................29
C. 探討splice site突變影響表面抗原的表現..........................................................30
a. 分析surface RNA是否進行剪接作用...........................................................30
b. 破壞splice donor site SD1741對表面抗原RNA表現的影響.........................32
c. 破壞splice donor site SD1485對表面抗原RNA表現的影響........................32
d. 破壞splice acceptor site對表面抗原表現的影響..........................................33
e. 插入內隱子對於G1740A突變所造成的表面抗原表現下降補救能力的探討....................................................................................................................33
f. 分析splice donor site與U1 snRNA之間的配對情形對表面抗原表現
的影響............................................................................................................33
g. 當splice acceptor site被破壞時,splice donor site與U1 snRNA之間
的配對能力對表面抗原表現的影響以及轉染互補的U1 snRNA對
SD 1741 minus突變補救能力的探討............................................................35
肆. 討論............................................................................................................................36
A. PTB對表面抗原表現的影響...............................................................................36
B. 討論PREαstem loop對HBV表面抗原表現有影響...........................................36
C. 剪接作用對HBV表面抗原表現的影響..............................................................36
D. 插入內隱子對於G1740A突變所造成的表面抗原表現改變補救的能力........37
E. 破壞剪接受位對表面抗原表現的影響...............................................................37
伍. 參考文獻.................................................................................................................39
陸. 表格............................................................................................................................46
表格一:本論文中所使用的引子.............................................................................46
表格二:分析SD1485-SA1770剪接形式的RNA,所使用之病人RNA檢體............48
柒. 圖形............................................................................................................................49
圖 1:HBV全長基因體表現質體中各種RNA與HBV探針雜交後,
經過S1 nuclease定位法後所形成的區域大小。...................................................49
圖 2:Myc-CAT fusion RNA與EGFP RNA與HBV探針雜交後,
經過S1 nuclease定位法後所形成的區域大小。..................................................50
圖 3:HBV表現質體(pSV HBV(MB 3047)、pPreS.S.(MB 4122)、
pCMV-S(MB 4126)、pPreS.S PRE(+)Int(β)(MB 4254)、
pSVpA-PreS.S(MB 5057)。................................................................................51
圖 4:建構表面抗原表現質體pSVpA-PreS.S(MB 5057)、pSk-4XpolyA
HBV 937-88(MB 5072)、pGEM-HBV 937-88(MB 5073)。............................52
圖 5:建構校正轉染效率之共轉染質體(pSV-EGFP-N2(MB 5108)、
pSVpoly EGFP-N2(MB 5110))。.........................................................................53
圖 6:建構PRE上被報告具有功能序列的突變質體。..................................................54
圖 7:建構剪接供位突變之HBV全長表現質體或表面抗原表現質體。.....................55
圖 8:建構剪接受位上的突變表現質體。.......................................................................56
圖 9:建構剪接供位/受位突變之表面抗原表現質體。..................................................57
圖 10:建構插入內含子時剪接供位的突變表現質體。.................................................58
圖 11:建構U1 snRNA 表現質體以及配合SD 1741 minus的突變U1 snRNA
表現質體................................................................................................................59
圖 12: 建構偵測EGFP RNA 所使用的S1 nuclease mapping探針質體。......................60
圖 13: 建構偵測HBV RNA所使用的S1 nuclease mapping探針質體。.........................61
圖 14:利用不同S1 nuclease mapping探針偵測surface RNA。....................................62
圖 15:在表面抗原表現質體的pre-S2啟動子前插入SV40 polyA訊號對產
生之RNA的影響。................................................................................................63
圖 16:評估作為校正轉染效率基準之質體。.................................................................64
圖 17:PRE序列突變對surface RNA表現的影響。......................................................65
圖 18:剪接供位突變與PRE序列突變對surface RNA表現的影響。.........................66
圖 19:大量表現spliceosome complex或RNA export相關蛋白質對HBV
表面抗原表現的影響。.........................................................................................67
圖 20:以pCMV-β為基準比較pcDNA3.1-PTB對HBV表面抗原表現的影響。......68
圖 21:以聚合酶鏈鎖反應分析HBV剪接RNA。..........................................................69
圖 22:經剪接的RNA以反轉錄聚合酶鏈鎖反應後的產物以ABI 3730自動核酸
序列分析。.............................................................................................................70
圖 23:在全長HBV表現質體pSV HBV(MB 3047)背景下, HBV序列上的突
變對RNA表現的影響。.........................................................................................71
圖 24:在表面抗原表現質體pPreS.S(MB 4122)與pCMV-S(MB 4126)背景
下,HBV序列上的突變對RNA表現的影響。.................................................72
圖 25:以北方墨點法分析在表面抗原表現質體pPreS.S(MB 4122)背景下,
HBV序列上的突變對RNA表現的影響。..........................................................73
圖 26:HBV序列上剪接訊號的突變對表面抗原RNA表現的影響。..........................74
圖 27:分析插入內隱子對於splice donor site SD 1741 minus突變所造成的表面抗
原表現補救能力。.................................................................................................75
圖 28:SD1741序列上的突變對RNA表現的影響。........................................................76
圖 29:SD1741序列上的突變對SA1770使用的影響。......................................................77
圖 30:當splice acceptor sites(SA1563、SA1770、SA2589、SA2666)同時被破壞時,
SD 1741序列上的突變對RNA表現的影響。........................................................79
圖 31:轉染可與SD 1741 minus突變互補的U1 snRNA對突變導致surface RNA
表現下降補救的能力。.........................................................................................80
捌. 附錄............................................................................................................................81
附圖 1:HBV結構與基因體。..........................................................................................81
附圖 2:HBV生活史。......................................................................................................82
附圖 3:目前已知存在於HBV基因體上的剪接訊號位置。.........................................83
附圖 4:剪接訊號與剪接作用過程。................................................................................84
附圖 5:mRNA運輸過程。...............................................................................................86
附圖 6:HBV基因體上的剪接訊號與PRE上cis-element的相對位置以及突變
示意圖。.................................................................................................................87
附圖 7:Splice donor site與U1 snRNA之間的關連性。................................................89
附圖 8:如圖17中的實驗過程,分別獨立進行3次實驗,以PhosphorImager進行顯像,並以ImageQuant version 5.2進行定量分析之結果。................................90
附圖 9:如圖19中的實驗過程,分別獨立進行3次實驗,以PhosphorImager進行顯像,並以ImageQuant version 5.2進行定量分析之結果。................................92
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