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研究生:李孟璋
研究生(外文):LEE, MENG-CHANG
論文名稱:在正常氧壓下探索人類肺上皮細胞中第二型缺氧誘導轉錄因子在染色質體上的結合位置及潛在轉錄活性
論文名稱(外文):Exploring Potential Transcription Functions of Hypoxia-InducibleFactor-2α in BEAS-2B Based on Its Enrichment on Chromatin under Normoxia
指導教授:蕭嘉陽
指導教授(外文):Shiau, Chia-Yang
口試委員:蕭嘉陽蘇遂龍張自忠白壽雄邱仲峯
口試委員(外文):Shiau, Chia-YangSu, Sui-LungChang, Tsu-ChungPai, Shou-HsiungChiou, Jeng-Fong
口試日期:2016-09-02
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
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:105
語文別:英文
論文頁數:74
中文關鍵詞:染色質絲免疫沉澱定序法 (ChIP-seq)第二型缺氧誘導轉錄因子 (HIF-2α)N端活化區域 (N-TAD)
外文關鍵詞:Chromatin immunoprecipitation sequencing (ChIP-seq)Hypoxia-inducible factor-2α (HIF-2α)N-terminal activation domain (N-TAD)
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透過染色質絲免疫沉澱定序法分析已經揭露了一些在缺氧狀態下的癌症細胞中,其缺氧誘導轉錄因子在全基因組中會結合的位置。然而,逐漸地有研究指出在正常氧壓下的癌症及癌症幹細胞中,也發現有第二型缺氧誘導轉錄因子的存在及作用。在本研究中,亦闡明了第二型缺氧誘導轉錄因子在正常氧壓下對人類支氣管上皮細胞株BEAS-2B (ATCC® CRL9609™)的重要性。此外BEAS-2B尚具有部分細胞多能性之標記及特徵,如OCT4和NANOG的表達及sphere 的形成。第二型缺氧誘導轉錄因子可協助維持OCT4的表達量。透過分析第二型缺氧誘導轉錄因子的富集區域及其所註解的基因,發現到第二型缺氧誘導轉錄因子主要是利用結合在增強子(enhancer)的位置來調節基因,同時揭露了新的結合基序(motifs)、可能與第二型缺氧誘導轉錄因子合作的異源二聚體蛋白質,另外亦提供了其有可能參與的基因本體(gene ontology)及生物途徑,例如在與OCT4有關的細胞多能性及癌症機轉上,以上的結果代表著第二型缺氧誘導轉錄因子在正常氧壓中可能扮演著多重角色。在第二型缺氧誘導轉錄因子其結合的區域中僅有11.9%具有缺氧反應序列 (HRE) RCGTG,這可能說明了第二型缺氧誘導轉錄因子在正常氧壓下的BEAS-2B中,主要是以非典型的缺氧作用機轉來調控基因。缺氧環境下,對於原本第二型缺氧誘導轉錄因子在正常氧壓下的富集位置,其會造成再加強,或者是較少影響,抑或是有減少富集之現象。剔除N端活化區域(N-TAD)的第二型缺氧誘導轉錄因子會造成二個在註解為ELN 及ANKRD31基因的富集區域之報導能力大量下降,而此兩段區域本身的第二型缺氧誘導轉錄因子的富集程度是較不受缺氧狀態影響的。缺氧環境下所研究的第二型缺氧誘導轉錄因子,可能會模糊了原本是由N端活化區域所主導的調控基因或機轉,並且誤歸於是缺氧所引起的反應。此外,附基因修飾試劑 trichostatin A (TSA)可提升OCT4在轉錄及蛋白質層次的表達,這暗示著附基因調控機轉在BEAS-2B的細胞多能性上扮演了某種程度的角色。探索第二型缺氧誘導轉錄因子在正常氧壓下的功能及機轉有助於解析它在細胞多能性及惡性腫瘤上所扮演的角色。


Chromatin immunoprecipitation sequencing (ChIP-seq) analysis has disclosed global genomic binding of HIFs in some cancer cells under hypoxia. However, constituent expression of active HIF-2α in cancers and cancer stem cells under normoxia was progressively demonstrated. In this research, the significance of HIF-2α was illustrated in the human bronchial epithelial cells BEAS-2B (ATCC® CRL9609™) under normoxia. In addition, some markers and feature of pluripotency such as OCT4, NANOG, and sphere formation were also detected in BEAS-2B. HIF-2α helped maintain the expression of OCT4. Analysis of the HIF-2α enriched regions and its annotated loci discovered a prevailing enhancer role of HIF-2α, de novo motifs, potential heterodimer partners, and involvement of gene ontology and pathways, such as in the OCT4-regulated pluripotency and mechanisms of cancer, which indicated the versatile roles of HIF-2α in the normoxia. HIF-2α binding sites possessed only 11.9% of the core hypoxia response element (HRE) RCGTG, suggesting a predominant non-canonical mechanism in normoxic BEAS-2B. Hypoxia exerted encouraging, or minimal, or conflicting impacts on the HIF-2α enriched regions derived from normoxia. The truncated N-terminal transactivation domain (N-TAD) of HIF-2α jeopardized the reporting activity of two enriched fragments annotated to ELN and ANKRD31 whose HIF-2α enrichment was less influenced by hypoxia. Studies of HIF-2α under hypoxia might obscure some loci or mechanisms predominantly driven via N-TAD and mislead to the hypoxia-inducible features. In addition, epigenetic modification reagent trichostatin A (TSA) enhanced expression of OCT4 in transcript and protein levels, implicating, to some extent, the involvement of epigenetic mechanism in the pluripotency of BEAS-2B. Exploration of functions and mechanisms of HIF-2α under normoxia is beneficial for dissecting its roles in the pluripotency and malignancy.
Table of contents
Table of contents I
List of Figures V
List of Tables VII
List of Appendix VIII
摘要 IX
Abstract XI
1. Motives of research 1
2. Purposes of research 3
3. Literature review 4
3.1 Hypoxia-inducible factors (HIFs) play a key role to
response hypoxia 4
3.2 The structures of HIFs 5
3.3 The regulation mechanisms of HIFs 6
3.4 The roles of HIFs in biology 9
3.4.1 HIFs and glycolysis metabolism 9
3.4.2 HIFs and angiogenesis 10
3.4.3 HIFs and cancers 11
3.4.4 HIFs and stemness 13
3.5 chromatin immunoprecipitation sequencing (ChIP-seq) 15
3.6 ChIP-seq analysis of HIFs 16
4. Methods 18
4.1 Research framework 18
4.2 Materials and methods 21
4.2.1 BEAS-2B and HEK293 cells culture 21
4.2.2 Western blotting 21
4.2.3 Chromatin immunoprecipitation (ChIP) and polymerase
chain reaction (PCR) assay 22
4.2.4 ChIP-sequencing (ChIP-seq) analysis 24
4.2.5 Reporter assay 28
4.2.6 Knockdown assay 28
4.2.7 Reverse Transcriptase (RT) – PCR 29
4.2.8 Sphere culture/formation 29
4.3 Statistical analysis 30
5. Results 31
5.1 Features of pluripotency correlated markers and a
sphere formation of BEAS-2B under normoxia 31
5.2 ChIP-seq analysis of HIF-2α 35
5.3 Distribution of HIF-2α binding sites 39
5.4 Disparity of enrichment of HIF-2α between normoxia
and hypoxia 41
5.4.1 Verification of HIF-2α binding peaks under normoxia 41
5.4.2 Hypoxia effect to the enrichment against HIF-2α and
P300 derived from normoxia 41
5.5 Analysis of the activity of HIF-2α bound fragments 44
5.5.1 Verification of HIF-2α enriched fragments activity 44
5.5.2 Hypoxia effect to the activity of HIF-2α enriched
fragments derived from normoxia 44
5.5.3 Analysis of contributions of N-TAD and C-TAD of HIF-2α
to the activity of HIF-2α enriched fragments 45
5.6 Exploration of HIF-2α binding motifs 48
5.6.1 Nucleotide composition profile of HIF-2α binding peaks
of BEAS-2B 48
5.6.2 Analysis of HIF-2α binding motifs of BEAS-2B 48
5.6.3 Comparison with HIF-2α binding motifs between BEAS-2B
and 786-O 49
5.6.4 Exploration of HIF-2α potential heterodimer partners
of BEAS-2B 50
5.7 Analysis of gene ontology (GO), pathways and “Diseases and
Functions” of HIF-2α enriched loci involved in BEAS-2B 53
5.7.1 Analysis of GO 53
5.7.2 Analysis of pathways and “Diseases and Functions” 56
5.8 Hypoxia or trichostatin A (TSA) effect to the
pluripotency of BEAS-2B: OCT4 as marker 58
5.8.1 Hypoxia effect 58
5.8.2 TSA effect 58
6. Discussions 61
7. Limitation 64
8. Conclusions 65
9. References 67
Appendix



List of Figures
Figure 1 The schematic workflow of HIF-2α ChIP-seq of
normoxic BEAS-2B. 19
Figure 2 The workflow of analysis of hypoxia effect to
BEAS-2B. 20
Figure 3 The workflow of analysis of TSA effect to BEAS-2B. 20
Figure 4 The workflow of analysis of HIF-2α ChIP-seq. 27
Figure 5 Features of pluripotency related markers and a
sphere formation of BEAS-2B under normoxia. 33
Figure 6 An overlapping of putative target genes of HIF-2α
between BEAS-2B and 786-O and MCF-7. 38
Figure 7 Distribution of HIF-2α binding sites in BEAS-2B under
normoxia. 40
Figure 8 Hypoxia effect to the enrichment of HIF-2α and p300
of normoxic BEAS-2B. 43
Figure 9 Differential contributions of N-TAD and C-TAD of
HIF-2α to the activity of HIF-2α enriched fragments. 47
Figure 10 Exploration of HIF-2α binding motifs. 51
Figure 11 Hypoxia or trichostatin A (TSA) effect to the
pluripotency of BEAS-2B: OCT4 as marker. 60



List of Tables
Table 1 Top 15 of HIF-2α binding sites. 37
Table 2 Analysis of Gene Ontology. 55
Table 3 Analysis of pathways. 57



List of Appendix
Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions. Scientific Reports 2016 Jul 4;6:29311. doi: 10. 1038/srep29311

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