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研究生:王佑銘
研究生(外文):Wang, Yu-ming
論文名稱:缺氧環境下影響IRES介導蛋白轉譯調控之全基因組分析
論文名稱(外文):Whole genome profiling of hypoxia-induced, IRES-mediated translational regulation
指導教授:孫孝芳孫孝芳引用關係
指導教授(外文):Sun, H. Sunny
口試委員:曾大千陳琮明
口試委員(外文):Ta-Chien TsengTsung-Ming Chen
口試日期:2016-07-25
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:51
中文關鍵詞:轉譯起始核糖體進入位點缺氧核糖體定序
外文關鍵詞:Translation initiationIREShypoxiaRibosome profiling (Ribo-Seq)
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轉譯是一個經由核糖體讀取RNA模板進行蛋白質合成的重要生物過程,在正常的情況下,真核細胞是藉由5端帽結構開啟轉譯的起始,使得蛋白質生成;但是,當細胞在面對到壓力,像是缺氧狀態,一般轉譯的機制會被抑制,改走核糖體進入位點(Internal ribosome entry site, IRES)或是藉由真核起始因子4E2(Eukaryotic translation initiation factor 4E, eIF4E2)所主導的轉譯機制。本實驗室先前的研究發現,人類第九號纖維母細胞生長因子(Fibroblast growth factor 9, FGF9) 在缺氧的環境的刺激下,蛋白質表現地上升是透過IRES調控的轉譯機制,且FGF9過度表達對於結腸癌腫瘤發生的作用有著重要的角色。然而,目前對於真核生物在缺氧環境下,是如何透過 IRES的轉譯機制進行蛋白質轉譯尚不清楚。為了更進一步研究在缺氧環境下IRES介導轉譯的重要性,我們利用人類胚胎腎臟細胞株(Human Embryonic Kidney 293 cells, HEK293),培養於正常氧分壓(21% 氧氣量)或是缺氧環境(1%氧氣量),隨後進行核糖體定序(Ribosome profiling or Ribo-seq),以核糖體接合的位置作為蛋白質轉譯的基礎進行全基因組分析,經由轉譯體(translatomic)方式的分析過後,我們發現將近有900個基因在缺氧環境的刺激過後,轉譯的表現上調,其中,有215個基因被預測在5端非編碼區(Five prime untranslated region, 5’UTR)可能含有IRES,接下來我們更進一步利用生物資訊方式去分析,發現這群基因高度的與神經相關途徑或是疾病有關係。在這邊總和以上結果,此研究系統性的闡述了缺氧環境會啟動IRES轉譯機制,並且藉由IRES所調控的蛋白質生成在缺氧環境下對生物體來說是重要的。
Translation is a crucial biological process by which a ribosome reads an mRNA template for protein synthesis. Normally, eukaryotic cells use cap-dependent translation initiation to start the process of protein synthesis, However, if encounter hypoxic stress, cellular translation is initiated through Internal ribosome entry site (IRES)- and/or eIF4E2-mediated translations. Our previous study suggested that Fibroblast growth factor 9 (FGF9) expression is up-regulated during hypoxia through IRES-mediated translational activation and the hypoxia-induced, IRES-mediated FGF9 overexpression plays an important role in colon cancer tumorigenesis. However, the mechanism underlying eukaryotic IRES-mediated translation initiation in hypoxia remains controversial. To further evaluate the significance of eukaryotic IRES-mediated translation activation in hypoxia, HEK293 cells were cultured in either normoxic (21% O2) or hypoxic (1% O2) condition and followed by Ribosome profiling (Ribo-Seq) to obtain genome-wide ribosome position during translation initiation. Using translatomic approach, we found that translational activity of approximately 900 genes was up-regulated in hypoxia. Among them, 215 genes were predicted to contain IRES in their 5’ untranslated region (5’ UTR). Further computational annotation revealed that hypoxia significantly affects a group of genes participated in neuron-associated pathways or disorders. This study systemically profiles genes under hypoxia-induced, IRES–mediated translational activation and illustrates the importance of IRES-mediated control on protein synthesis in hypoxia.
摘要 II
Abstract III
致謝 IV
Table of contents 1
Introduction 4
1. Influence of hypoxia 4
1.1 Metabolic and cellular energy change in hypoxia 4
1.2 Pathophysiological conditions in hypoxia 4
1.3 Gene expression in hypoxia 5
2. Protein translation regulation 6
2.1 Canonical cap-dependent translation 6
2.2 eIF4E2-mediated translation 7
2.3 IRES-mediated translation 8
3. Translatome analysis 8
3.1 Progress of translatome analysis 8
3.2 Strengths and limitations of Ribo-seq 10
4. Expression of fibroblast growth factor 9 11
4.1 Fibroblast growth factor family 11
4.2 Physiological functions of FGF9 12
4.3 Regulation of FGF9 12
4.4 Hypoxia-induced protein expression of FGF9 13
Research aims 14
Materials and Methods 15
1. Cell culture 15
2. Protein preparation 15
3. Plasmid DNA extraction 15
4. Western blot 16
5. shRNA Knockdown 16
6. Ribosome profiling library preparation 17
7. Enzyme-linked immunosorbent assay (ELISA) 18
8. Bioinformatics analysis 18
9. Statistical analysis 19
Results 20
1. The hypoxia-induced translational activation of FGF9 protein expression is mainly through IRES-mediated mechanism 20
2. Whole genome profiling of hypoxia-induced translation regulation 20
3. Confirmation of hypoxia-induced, IRES-mediated translational regulation of FGF9 21
4. Identification of genes under hypoxia-induced, IRES-mediated translational regulation 22
5. Annotation of genes potentially under hypoxia-induced, IRES-mediated translational activation. 22
Discussion 24
Ribo-seq can’t directly give the message about whether the signal from cap-dependent or cap-independent translation. 24
The intersection of translation efficiency (TE) up-regulated group with predicted IRES-containing genes can not fully exclude eIF4E2-mediated translation interference. 24
This study shows new insight of IRES-mediated translation in hypoxia 25
mTOR signaling pathway has association with variety of cell process 26
IRES activity may associate with time course of hypoxia treatment and cell line. 27
Figures 28
Figure 1. The hypoxia-induced translational activation of FGF9 protein expression is mainly through IRES-mediated mechanism 29
Figure 2. Sample preparation 30
Figure 3. FGF9 expression is activated through the IRES element in hypoxia 31
Figure 4. Translation efficiency (TE) analysis. 32
Figure 5. Annotation of genes under hypoxia-induced, IRES-mediated translational activation. 35
Figure 6. Schematic of the translation initiation model in normoxia and hypoxia. 36
Tables 37
Table 1. Reads summary generated by Ribo-seq and RNA-seq 37
Table 2. Mapping summary of Ribo-seq and RNA-seq 38
Reference 39
Appendix 51
Appendix figure 1. The cross of translation efficiency up-regulated genes with reported IRES-containing genes. 51
Appendix figure 2. The cross of TE up-regulated genes with hypoxia heavy data. 51
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