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研究生:黃曉寧
研究生(外文):Hsiao-Ning Huang
論文名稱:miR-200c和GATA4調控人類胚胎幹細胞的更新與分化
論文名稱(外文):miR-200c and GATA binding protein 4 regulate human embryonic stem cell renewal and differentiation
指導教授:呂仁
指導教授(外文):Jean Lu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:93
中文關鍵詞:胚胎幹細胞類胚體miR-200cGATA結合蛋白4細胞凋亡分化上皮-間質轉化
外文關鍵詞:embryonic stem cellsembryoid bodymiR-200cGATA binding protein 4apoptosisdifferentiationepithelial-mesenchymal transition
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人類胚胎幹細胞具有自我更新和分化成體內各種不同形態細胞的特性,然而目前對造成其特性的分子機制尚未完全了解。人類胚胎幹細胞可以分化形成類胚體,類胚體具有分化成外胚層,中胚層和內胚層的能力。微型 RNA 是一群不會產生蛋白質的 RNA能夠調控細胞內生物功能。本研究證實在 miR-200 家族中,miR-200c 在未分化的人類胚胎幹細胞有高度的表現量,當人類胚胎幹細胞走向分化類胚體階段時,miR-200c 的表現量降低。在人類胚胎幹細胞降低 miR-200c時會造成 GATA4 的表現量上升,並誘導細胞走向凋亡。相反的,當降低 GATA4 的表現量時會減緩人類胚胎幹細胞走向凋亡。miR-200c 能和 GATA4 的 3'UTR 結合,進而調控 GATA4 的表現量。此外,GATA4 的表現量下降會抑制類胚體形成。過度表現 miR-200c則會抑制類胚體形成並且抑制外胚層、內胚層和中胚層的表現量,此時只要額外增加 GATA4 的表現量,則會增加類胚體形成。成纖維細胞生長因子 (FGF)/ 激活素A (activin A)/Nodal 的訊息傳遞因子能維持人類胚胎幹細胞自我更新的能力。轉化生長因子-β(TGF-β)/激活素A / Nodal訊息傳遞因子能經由 SB431542 處理來調控 miR-200c 的表現量。過度表現 miR-200c 能部分提升被 SB431542 處理後的 Nanog/phospho-Smad2 表現量。當胚胎幹細胞走向分化的階段時,細胞會產生上皮-間質轉化 (EMT) 的現象,此外,降低 miR-200c 的表現量會促進人類胚胎幹細胞具有移動的能力以及誘導 N-cadherin、Slug 以及 Snai1 的表達量上升。我們的研究發現 miR-200c 和 GATA4 能調控人類胚胎幹細胞更新和分化的調控功能。研究 miR-200c 在調節 EMT 中所扮演的角色可以幫助我們了解發育過程的調控機制。
Human embryonic stem cells (hESCs) are functionally unique for their self-renewal and pluripotency, but the molecular mechanisms giving rise to these properties are not fully understood. hESCs can differentiate into embryoid bodies (EBs) containing ectoderm, mesoderm, and endoderm. MicroRNAs (miRNAs) are small non-coding RNAs regulating important cellular processes. In the miR-200 family, miR-200c was especially enriched in undifferentiated hESCs and significantly downregulated in EBs. We found knockdown of miR-200c in hESCs downregulated Nanog expression, upregulated GATA binding protein 4 (GATA4) expression, and induced hESC apoptosis. On the contrary, knockdown of GATA4 rescued hESC apoptosis induced by downregulation of miR-200c. We identified miR-200c directly targeted the 3’-untranslated region of GATA4. In addition, the downregulation of GATA4 significantly inhibited EB formation in hESCs. Overexpression of miR-200c inhibited EB formation and repressed the expression of ectoderm, endoderm, and mesoderm markers, which could partially be rescued by ectopic expression of GATA4. Fibroblast growth factor (FGF) and activin A/nodal signaling pathways can sustain hESC renewal in the absence of feeder layer. Inhibition of transforming growth factor-β (TGF-β)/activin A/nodal signaling by SB431542 treatment could downregulate the expression of miR-200c. Lastly, overexpression of miR-200c partially rescued the expression of Nanog/phospho-Smad2 that was downregulated by SB431542 treatment. Epithelial-mesenchymal transition (EMT) plays important roles during ESC differentiation. Knockdown of miR-200c promoted migration ability of hESCs and induced N-cadherin, Slug and Snai1 expression. In conclusion, our research uncovers the novel functions of miR-200c and GATA4 in regulating hESC renewal and differentiation. Moreover, investigation the role of miR-200c in regulating EMT helps us to understand the regulatory mechanism of the developmental process.
Table of contents

誌謝……………………………………………………………………………………i
中文摘要………………………………………………………………………………iii
Abstract……………………………………………………………………………….iv
Table of contents………………………………………………………………………vi
List of Tables…………………………………………………………………………ix
List of Figures…………………………………………………………………………x
Abbreviation……………………………………………………………………….xiii
Chapter 1. Introduction…………………………………………………………….1
1.1 Embryonic stem cells (ESCs) ………………………………………………...1
1.1.1 Transforming growth factor-β (TGF-β) signaling pathway maintaining
pluripotency of hESCs………………………………………………….1
1.1.2 EB differentiation as a model of early development………………….2
1.2 MicroRNAs in embryonic stem cells…………………………………………3
1.2.1 The biogenesis of miRNAs……………………………………………3
1.2.2 The roles of miRNAs expression in ESCs………………………………4
1.3 miR-200 family………………………………………………………………...6
1.3.1 The function of miR-200 family in ESCs……………………………..6
1.3.2 The miR-200 family and epithelial-mesenchymal transition (EMT)....6
1.3.3 The miR-200 family and tumor protein p53 (p53)……………………..8
1.4 GATA Binding Protein 4 (GATA4)…………………………………………..10
1.4.1 GATA transcription factor family……………………………………...10
1.4.2 The functions of GATA4………………………………………………11
1.5 Objectives………………………………………………………………………12

Chapter 2. Materials and Methods………………………………………………...13
2.1 Materials………………………………………………………………………...13
2.2 Cell lines and culture conditions………………………………………………..13
2.3 RNA extraction and quantitative real-time RT-PCR……………………………13
2.4 Protein extraction and Western blot analysis…………………………………...14
2.5 Embryoid body formation………………………………………………………15
2.6 Immunofluorescence assay……………………………………………………..16
2.7 Flow cytometry analysis………………………………………………………...16
2.8 Transfection assay………………………………………………………………17
2.9 Lentivirus production and hESC infection……………………………………...17
2.10 Luciferase reporter assay………………………………………………………..18
2.11 Cell migration and invasion assay………………………………………………19
2.12 Statistical analyses………………………………………………………………20

Chapter 3. Results…………………………………………………………………21
3.1 Examination of miR-200 family expression levels in hESCs………………….21
3.2 Downregulation of miR-200c decreased pluripotency markers and promoted the
expression of GATA4 in hESCs…………………………………………………21
3.3 GATA4 is a direct target of miR-200c………………………………………….22
3.4 The miR-200c-GATA4 pathway regulated hESC apoptosis…………………….23
3.5 Overexpression of miR-200c inhibited hESC differentiation and EB
formation……………………………………………………………………..25
3.6 Ectopic overexpression of GATA4 partially restored EB formation inhibited by
the overexpression of miR-200c…………………………………………………26
3.7 Overexpression of miR-200c partially restored the expression levels of
Nanog and phospho-Smad2 downregulated by SB431542…………………….27
3.8 Downregulation of miR-200c contributed to EMT-like phenotype in
hESCs……………………………………………………………………………28

Chapter 4. Discussion……………………………………………………………….31
References……………………………………………………………………………...41
Tables…………………………………………………………………………………..57
Figures…………………………………………………………………………………58

List of Tables
Table 1. Primers used for qRT-PCR……………………………………………………57

List of Figures
Figure 1. The location and sequences of the miR-200 family………………………….58
Figure 2. The expression levels of the miR-200 family in HUES6 cells………………59
Figure 3. The expression of miR-200c was crucial for maintaining hESC
pluripotency………………………………………………………………….60
Figure 4. Downregulation of miR-200c decreased the expression levels of
pluripotent markers in HUES6 cells…………………………………………62
Figure 5. Knockdown of miR-200c decreased the pluripotent markers
in H9 cells……………………………………………………………………63
Figure 6. Downregulation of miR-200c promoted GATA4 expression
in H9 cells……………………………………………………………………64
Figure 7. miR-200c directly targeted GATA4…………………………………………65
Figure 8. miR-200c directly targeted GATA4 and regulated GATA4 expression in H9
cells…………………………………………………………………………..66
Figure 9. Knockdown of miR-200c induced hESC apoptosis after day 8
post-infection………………………………………………………………...67
Figure 10. Downregulation of GATA4 rescued the apoptosis triggered by
anti-miR-200c in H9 cells………………………………………………….69
Figure 11. Downregulation of GATA4 partially rescued HUES6 renewal inhibited by
the expression of anti-miR-200c…………………………………………...71
Figure 12. Downregulation of miR-200c upregulated the expression levels of p53
in H9 cells…………………………………………………………………..72
Figure 13. Downregulation of p53 rescued the apoptosis triggered by
anti-miR-200c in H9 cells………………………………………………….73
Figure 14. Overexpression of miR-200c hampered the EB formation efficiency in H9
cells in differentiated medium……………………………………………...75
Figure 15. Overexpression of miR-200c decreased the sizes of EBs
in the HUES6 cells…………………………………………………………77
Figure 16. Changes in miR-200c levels affected the expression levels of differentiation
markers…………………………………………………………………….79
Figure 17. Knockdown of GATA4 hampered the EB formation efficiency
in H9 cells………………………………………………………………….81
Figure 18. The expression of GATA4 was required for EB formation and
overexpression of GATA4 can rescue EB formation inhibited by the
overexpression of miR-200c………………………………………………82
Figure 19. Overexpression of GATA4 rescued the expression of multiple differentiation
markers downregulated by the presence of miR-200c mimics…………….83
Figure 20. SB431542 treatment changed the cellular morphology of hESCs and
decreased the expression levels of pluripotent markers……………………84
Figure 21. Overexpression of miR-200c partially rescued the differentiated
morphology and the expression of Nanog and phospho-Smad2 altered by
the treatment of the TGF-β pathway inhibitor SB431542 in H9 cells…….85
Figure 22. Overexpression of miR-200c partially rescued the phospho-Smad2
/Nanog/Oct4 levels in the HUES6 cells treated with SB431524………….86
Figure 23. Downregulation of miR-200c promoted EMT phenotype in undifferentiated
hESCs………………………………………………………………………87
Figure 24. Knockdown of miR-200c affected migration and invasion ability of
hESCs……………………………………………………………………89
Figure 25. The roles of miR-200c in hESCs………………………………………….90
Figure 26. The mechanism of miR-200c pathway regulated EMT and differentiation
in hESCs…………………………………………………………………..91
Figure 27. The mechanism of miR-200c pathway regulated apoptosis in hESCs……92
Figure 28. The mechanism of miR-200c-GATA4 pathway regulated EB formation/differentiation in EB model………..93

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