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系統識別號 U0026-0812200915075432
論文名稱(中文) 人類轉錄因子YY1/Polycomb基團蛋白/去氧核糖核酸轉甲基酶複合體經由表觀遺傳的調控而抑制人類轉錄因子CCAAT/Enhancer-binding Protein delta 的基因活性
論文名稱(英文) Epigenetic Silencing of CCAAT/Enhancer-binding Protein delta Activity by YY1/Polycomb Group/DNA Methyltransferase Complex
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 97
學期 2
出版年 98
研究生(中文) 柯瓊媛
研究生(英文) Chiung-Yuan Ko
電子信箱 s5892103@mail.ncku.edu.tw
學號 s5892103
學位類別 博士
語文別 英文
論文頁數 92頁
口試委員 指導教授-張文昌
指導教授-王育民
口試委員-賴明德
口試委員-呂增宏
召集委員-劉校生
口試委員-阮麗蓉
口試委員-洪文俊
口試委員-蔡坤志
中文關鍵字 甲基化  表觀遺傳 
英文關鍵字 Epigenetic  CEBPD  Methylation  Polycomb  YY1  SUZ12 
學科別分類
中文摘要 CEBPD基因是屬於C/EBP家族蛋白中的一員,而這類蛋白已知是與組織的分化、代謝及免疫反應有關的轉錄因子。由先前的研究中指出,CEBPD參與調控脂肪生成作用及由免疫刺激所引起的急性反應。然而最近也有報導指出CEBPD可造成細胞生長停滯而參與在分化過程中,並且也可調控一些前細胞凋亡基因的表現,以上結果顯示了CEBPD可能具有腫瘤抑制者的功能。已知在人類乳癌與急性骨髓白血病病人的檢體中,CEBPD基因的表現量降低或是功能喪失。在本研究裡,我們也在子宮頸癌及肝癌病人的檢體中發現到CEBPD基因的表現量降低。然而對於在腫瘤發生過程中,CEBPD基因是如何被默化的,其詳細的分子機制目前仍不清楚。另一方面,由先前研究已知,表觀遺傳的作用是透過對於啟動子上CpG islands的過度甲基化而非改變DNA序列的方式,去抑制腫瘤抑制因子的活性。近期也有報導指出,透過對於一些在癌化過程中的關鍵基因上CpG islands的過度甲基化而抑制其活性,對於癌化的過程是扮演著重要的角色。在本研究中,首先我們利用DNA轉甲基酶抑制劑,5’-azaC,證明了CpG islands的過度甲基化會造成CEBPD基因的默化;此外,我們也利用了染色質免疫沉澱技術,證明了屬於PRC2複合蛋白中的EZH2及SUZ12可以結合至CEBPD基因的啟動子區域上而參與CEBPD基因的默化作用。更進一步,我們也證明了 SUZ12會抑制CEBPD啟動子的活性,並且可透過CEBPD啟動子區域上的CpG islands而增加其甲基化的程度。然而分子層面上的研究結果也吻合了在子宮頸癌和肝癌病人的檢體上,SUZ12和CEBPD基因表現的相對量和CEBPD基因默化之間的關聯性。最後,我們更進一步發現轉錄因子YY1可以透過和SUZ12間的交互作用而將PcG蛋白和DNA甲基轉移酶吸引至CEBPD啟動子區域上,而參與在CEBPD基因默化的過程中。綜合以上結果,我們不僅證明SUZ12可透過抑制CEBPD的表現而促進腫瘤形成,也釐清了在CEBPD啟動子區域上,SUZ12和DNA甲基轉移酶經由YY1所造成的基因默化路徑。
英文摘要 CCAAT/enhancer-binding protein  (CEBPD) belongs to the CCAAT/enhancer-binding protein family members that function as transcription factors acting in tissue differentiation, metabolism, and immune responses. Previous studies have shown that CEBPD participates in controlling adipogenesis and the acute phase response to inflammatory stimuli. Recently, CEBPD has been reported as a tumor suppressor because it induces growth arrest for differentiation and plays a crucial role as an inducer of pro-apoptotic gene. The “loss of function” alternations in CEBPD gene expression have been reported in primary human breast cancer and acute myeloid leukemia. In this study, we further demonstrated that CEBPD gene expression is down-regulated in cervical cancer and hepatocellular carcinoma patient samples. However, the detail of CEBPD gene silencing remains unknown in tumorigenesis. Hypermethylation of CpG islands, an epigenetic event that is not accompanied by changes in DNA sequence, represents an alternative mechanism different from deletions or mutations to inactivate tumor suppressor genes. Recent evidence supports the notion that CpG islands hypermethylation, via the silencing of key cancer-related genes, plays a major causal role in cancer. Therefore, we used the DNA methyltransferase inhibitor, 5’-azaC, to demonstrate that hypermethylation of CpG islands is responsible for CEBPD gene silencing, and we showed that the polycomb repressive complex 2 (PRC2) components, enhancer of zeste homolog 2 (EZH2) and suppressor of zeste 12 (SUZ12), bind to CpG islands of CEBPD promoter region by the in vivo binding assay, ChIP assay. In addition, we demonstrated that SUZ12 silences CEBPD promoter activity and enhances the methylation level of exogenous CEBPD promoter in vivo through the proximal CpG islands. Moreover, this molecular approach is consistent with the opposite mRNA expression pattern between SUZ12 and CEBPD in cervical cancer and hepatocellular carcinoma patients. The CEBPD down-regulation is also coincide with its promoter hypermethylation in these tumor samples. Finally, we demonstrated that Yin Yang 1 (YY1) physically interacts with SUZ12 in vivo. From the knockdown approach, we proved that YY1 can act as a mediator to recruit the PcG proteins and DNMTs to participate in the CEBPD gene silencing process. Taking these results into consideration, we not only demonstrated the advantage of SUZ12-silenced CEBPD expression in tumor formation but also clarify an in vivo evidence for YY1-mediated silencing paths of SUZ12 and DNMTs on the CEBPD promoter.
論文目次 Abstract..................................................i
Abstract in Chinese.....................................iii
Acknowledgments...........................................v
Contents.................................................vi
Abbreviation list.........................................x

Chapter 1 Introduction
1.1 CCAAT/Enhancer binding protein family.................1
1.1.1 CCAAT/Enhancer binding protein delta (CEBPD)........2
1.1.2 The role of CEBPD in acute phase response...........3
1.1.3 CEBPD in the regulation of cyclooxygenase-2 (COX-2) expression................................................3
1.1.4 CEBPD in the tumorigenesis..........................5
1.2 Epigenetic systems....................................6
1.2.1 Polycomb group (PcG) proteins.......................7
1.2.1.1 The Polycomb repressive complex 2 (PRC2)..........7
1.2.1.2 Recruitment of PcG complexes to their targets.....8
1.2.1.3 Silencing mechanisms of PcG proteins..............9
1.2.2 DNA methylation....................................11
1.2.2.1 DNMTs and MBPs...................................12
1.2.2.2 Mechanisms of DNA methylation-mediated transcriptional repression...............................13
1.3 Epigenetics and cancer...............................15
1.4 Specific aims........................................16

Chapter 2 Materials and methods
2.1 Materials............................................17
2.2 Plasmids.............................................17
2.3 Methods..............................................18
Cell Culture and Treatment...............................18
Tissue Samples...........................................18
Fluorescence-activated Cell Sorting (FACS) Analysis......19
Plasmid Transfection and Reporter Gene Assay.............19
Reverse Transcription Polymerase Chain Reaction (RT-PCR).19
Western Blot Analysis....................................20
Small Interfering RNAs (siRNA) Assay.....................21
Sodium Bisulfite Modification of Genomic DNA/Methylation-specific PCR.............................................21
Chromatin Immunoprecipitation (ChIP) and re-ChIP Assay...22
DNA Affinity Precipitation Assay (DAPA)..................23
Soft Agar Assay..........................................24
Immunofluorescence Analysis..............................24

Chapter 3 Results
CEBPD induces cell death and inhibits cell proliferation and transformation .......................................25
DNA methyltransferase inhibitor reverses CEBPD expression25
PcG proteins bind to CEBPD promoter in vivo..............26
SUZ12 plays a repressive role in CEBPD gene transcription27
SUZ12 increases the methylation level of CEBPD promoter in vivo.....................................................28
SUZ12 and EZH2 attenuate mitogen-induced CEBPD expression29
Opposite expression of SUZ12 and CEBPD mRNA in human cervical cancer and HCC..................................29
CEBPD can repress the SUZ12-induced tumorigenic phenotype31
PcG proteins and DNMTs can be recruited to CEBPD promoter region through YY1.......................................31
YY1 represses CEBPD gene expression through promoter methylation..............................................33
Recruitment of SUZ12 through YY1 represses CEBPD transcription............................................33

Chapter 4 Discussion....................................35
References...............................................44
Figures
Figure 1. CEBPD induces cell death........................56
Figure 2. Overexpression of CEBPD attenuates cell proliferation and transformation.........................57
Figure 3. Sequence analysis of CEBPD gene and its promoter region...................................................58
Figure 4. DNA methyltransferase inhibitor, 5-AzaC,
reactivates endogenous CEBPD gene expression.............59
Figure 5. PRC2 proteins, SUZ12 and EZH2, bind to CpG islands of CEBPD promoter in vivo........................60
Figure 6. SUZ12 repress CEBPD transcription through its promoter regulation......................................61
Figure 7. SUZ12 plays a negative role in CEBPD transcription............................................62
Figure 8. SUZ12 can increase DNA methylation level of CEBPD promoter.................................................63
Figure 9. SUZ12 and EZH2 substantially lost their DNA binding activity in PMA- or EGF-treated cells............64
Figure 10.Increase of SUZ12 and EZH2 negatively regulate EGF or PMA-induced CEBPD promoter activity...............65
Figure 11.Opposite expression pattern of SUZ12 and CEBPD in human cervical cancer.................................66
Figure 12.Opposite expression pattern of SUZ12 and CEBPD in human HCC.............................................68
Figure 13.Statistical results of clinical samples........70
Figure 14.Overexpression of CEBPD blocks SUZ12-induced transformation activity..................................71
Figure 15.SUZ12 and DNMTs can be recruited to CEBPD promoter region through YY1 binding motifs...............72
Figure 16.Loss-of YY1 expression increases CEBPD gene expression...............................................75
Figure 17.YY1 functions in the SUZ12-mediated repression of the CEBPD gene........................................77
Figure 18.Differentiation inducers could activate CEBPD and cyclin-dependent kinases inhibitors expression.......78

Appendixes...............................................79
Curriculum vitae.........................................91
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