探討丙戊酸活化Oct4啟動子的機制

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李珮寧(Pei-Ning Li) 查詢紙本館藏

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論文名稱

探討丙戊酸活化Oct4啟動子的機制
(Defining the mechanisms mediating valproic acid enhanced Oct4 promoter activity)

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摘要(中)

細胞經由表達特定的轉錄因子，包含Oct4、SOX2、Klf4、c-Myc，使得細胞能夠重新編程產生誘導型多能性幹細胞，這類型的細胞可用來修補受損的組織，治療目前無法以傳統醫療治癒的疾病，例如：杜顯氏肌肉萎縮症，這項技術的優點在於避免了器官移殖可能發生的病人免疫排斥和傳統使用胚胎幹細胞的倫理道德問題，然而目前體細胞重新編程的技術仍存在一些待克服的問題，例如，使用反轉錄病毒作為載體，可能造成外源基因隨機插入染色體，進而干擾內源基因正常的表達，另一個潛在的問題則是產生誘導型多能性幹細胞的效率依然很低。因此，近年來有文獻指出加入小分子化合物-丙戊酸 (VPA)，是一種組蛋白去乙醯酶抑制劑能夠增加體細胞重新編程的效率。在我們實驗室先前的研究中證實，丙戊酸會作用在Oct4啟動子的賀爾蒙反應調控區域 (HRE) 來活化Oct4啟動子的活性，但丙戊酸調控Oct4啟動子的機制還不清楚。因此，在這篇研究中，我們證明丙戊酸不是經由抑制組蛋白去乙醯化來調控Oct4啟動子的活性，我們發現丙戊酸會經由誘發PI3K/Akt/mTOR訊息傳遞來活化Oct4啟動子，更進一步我們證明，對丙戊酸會影響某些特定核受體 (NRs)，例如，減緩TR2和COUP-TFΠ對Oct4啟動子的抑制，以及增強PPARδ對Oct4啟動子的活性，來活化Oct4啟動子。我們認為在體細胞重新編程的過程中，丙戊酸是透過活化PI3K/Akt/mTOR訊息傳遞來活化Oct4啟動子進而提升產生誘導型多能性幹細胞的效率。

摘要(英)

Reprograming of somatic cells into induced pluripotent stem cells (iPSC) by expressing Oct4, Sox2, Klf4, and c-Myc has paved the way for producing patient-specific pluripotent cells to treat inherited diseases, such as Duchenne muscular dystrophy. However, current reprogramming approach has some risks, such as viral transduction caused random integration of multiple pro-viral copies and low efficiency. Recently, it was shown that a small compound called valporic acid (VPA), a histone deacetylase (HDAC) inhibitor, could improve reprogramming efficiency. Our previous study had shown that VPA can enhance Oct4 promoter activity by targeting its proximal hormone response element (HRE), but the underlying mechanism is not clearly defined. In this study, we found that inhibition of HDACs might play a minor role in the VPA mediated activation of Oct4 promoter. We discovered that VPA activated Oct4 promoter through inducing the PI3K/Akt/mTOR signaling pathway. The proximal HRE of Oct4 promoter was targeted by several nuclear receptors and we found that VPA reversed the repressive effect of some NRs, such as TR2 (nuclear receptor subfamily 2, group C, member 1) and COUP-TFII (nuclear receptor subfamily 2, group F, member 2), but enhanced the inducing effect of other NRs, including PPARδ (peroxisome proliferator activator receptor delta). We concluded that VPA triggered PI3K/Akt/mTOR signaling plays critical role in activating Oct4 promoter activity during somatic reprogramming.

關鍵字(中)

★ 丙戊酸

關鍵字(英)

★ VPA
★ Oct4
★ TR2
★ PPARδ
★ PI3K/Akt/mTOR

論文目次

一、緒論 .............................................................. 1
1-1、幹細胞 (Stem cells) 特性 ........................................................................................... 1
1-2、 Oct4 調控與幹細胞的多能性 (pluripotency)............................................................. 2
1-3、誘導型多能性幹細胞 (Induced pluripotent stem cells, iPSCs) ................................. 4
1-4、丙戊酸 (Valproic acid) ................................................................................................ 5
1-5、研究動機與目的 .......................................................................................................... 6
二、實驗材料和方法 .................................................... 7
2-1、細胞株 .......................................................................................................................... 7
2-1-1、老鼠肌纖維母細胞：Mouse myoblast cells (C2C12) ................................................. 7
2-1-2、老鼠胚胎癌細胞：Mouse embryonic carcinoma cells (P19 EC) ................................ 8
2-1-3、老鼠多能性胚胎幹細胞：Mouse pluripotent embryonic stem cell (ES-D3) .............. 9
2-1-4、老鼠纖維母細胞細胞：Mouse fibroblast (STO) ......................................................... 9
2-2、載體構築 (Cloning) ..................................................................................................... 9
2-2-1、載體構築 (Cloning) ...................................................................................................... 9
2-2-2、聚合酶鏈鎖反應 (PCR, Polymerase Chain Reaction) ............................................... 11
2-2-3、聚合酶鏈鎖反應產物的修飾 ..................................................................................... 11
2-2-4、插入 (Insert) DNA 的純化 ......................................................................................... 11
2-2-5、插入 DNA 或載體 DNA 的聚合酶反應 (Klenow) ................................................... 11
2-2-6、載體 DNA 的 5’端去磷酸根反應 (C.I.P) ................................................................. 12 II

2-2-7、接合反應 (Ligation) ................................................................................................... 12
2-2-8、大腸桿菌的轉型作用 (Transformation) .................................................................... 12
2-2-9、質體 DNA 的萃取 ...................................................................................................... 12
2-2-10、篩選 (Screening) ........................................................................................................ 13
2-3、 RT-PCR ...................................................................................................................... 13
2-3-1、 Total RNA 製備 .......................................................................................................... 13
2-3-2、反轉錄酶反應 (RT, Reverse Transcriptase) .............................................................. 13
2-3-3、聚合酶連鎖反應 (PCR, Polymerase Chain Reaction) ............................................... 14
2-4、 Real Time PCR 定量實驗 .......................................................................................... 15
2-5、轉染實驗 .................................................................................................................... 15
2-5-1、細胞培養 ..................................................................................................................... 15
2-5-2、轉染作用 (Transfection) ............................................................................................ 16
2-5-3、螢火蟲冷光活性方法 (Luciferase Activity Assay) ................................................... 16
2-6、體外蛋白質表達系統 (TNT Coupled Transcription/ Translation Systems) ............ 16
2-7、凝膠遷移滯後實驗（EMSA, electrophoretic mobility shift assays） ..................... 17
2-7-1、黏合 (Annealing) ........................................................................................................ 17
2-7-2、 DNA 探針的標定(labelling) ....................................................................................... 17
2-7-3、 DNA 探針的純化 ....................................................................................................... 18
2-7-4、凝膠製備 (Gel Casting) ............................................................................................. 18
2-7-5、蛋白質和核酸鍵結 (Protein-DNA binding) .............................................................. 19
2-7-6、 DNA 聚丙烯酰胺凝膠電泳 (DNA-PAGE) 和放射線偵測 ..................................... 19
2-8、西方墨點實驗 (Western blot) ................................................................................... 19
2-8-1、 Total Protein Lysate 的製備 ....................................................................................... 19
2-8-2、 SDS-聚丙烯酰胺凝膠電泳 (SDS-PAGE) ................................................................. 19
2-8-3、 Blocking 以及 Antibody 辨識 .................................................................................... 20
2-8-4、蛋白質脫附 (Striping) ................................................................................................ 20 III

2-9、染色質免疫沉澱 (CHIP, Chromatin immunoprecipitation assay) ........................... 21
2-9-1、細胞交互鍵結的固定 (Fixation of Cross-Linked Cells) ........................................... 21
2-9-2、染色質交互鍵結的製備 (Preparation of Cross-Linked Chromatin) ......................... 21
2-9-3、 Protein A from Staphylococcus aures 製備與置換..................................................... 22
2-9-4、染色質免疫沉澱 (Chromatin immunoprecipitation) ................................................. 22
2-9-5、 DNA 的萃取 ............................................................................................................... 23
三、實驗結果 ......................................................... 24
3-1. VPA 間接透過抑制 HDACs 來影響 Oct4 promoter 的活性 ................................... 24
3-2. Oct4 上游近端增強子調控區域不是 VPA 主要影響 Oct4 promoter 活性的區域 24
3-3. 核接受體 (NRs) -TR2 會直接地結合在 Oct4 proximal promoter 的 HRE 區域，
PPARδ 則不會 ........................................................................................................... 25
3-4. NRs 參與調控 Oct4 promoter 的機制中，TR2 扮演抑制者、PPARδ 則扮演活化
者的角色 .................................................................................................................... 26
3-5. VPA 降低 TR2 和 Oct4 promoter 之間的鍵結，且減緩 TR2 抑制 Oct4 promoter
的活性，但不影響 PPARδ 和 Oct4 promoter 之間的鍵結 ..................................... 27
3-6. 在調控 Oct4 promoter 的機轉中，TR2、PPARδ 可能扮演重覆性的角色 ........... 28
3-7. VPA 會增強細胞內 PI3K/Akt/mTOR 的訊息傳遞 ................................................. 28
3-8. VPA 經由影響 PI3K/Akt/mTOR 的訊息傳遞來減緩 TR2 對 Oct4 promoter 活性
的抑制 ........................................................................................................................ 29
3-9. VPA 調控 Oct4 的表現具有階段性的現象，在多能性的細胞中，VPA 會抑制
Oct4 的表現 ............................................................................................................... 30
四、討論 ............................................................. 31
五、圖表 ............................................................. 36
圖一、VPA 間接透過抑制 HDACs 來影響 Oct4 promoter 的活性 ................................. 36 IV

圖二、Oct4 近端增強子調控區域不是 VPA 主要影響 Oct4 promoter 活性的區域 ...... 37
圖三、核接受體 (NRs) -TR2 會直接地結合在 Oct4 的 HRE 區域，PPARδ 則不會 ... 38
圖四、NRs 參與調控 Oct4 promoter 的機制中，TR2 扮演抑制者，PPARδ 則扮演活
化者的角色 ................................................................................................................ 39
圖五、VPA 降低 TR2 和 Oct4 promoter 之間的作用，且減緩 TR2 抑制 Oct4 promoter
的活性，但不影響 PPARδ 和 Oct4 promoter 之間的作用 ..................................... 40
圖六、在調控 Oct4 promoter 的機轉中，TR2、PPARδ 可能扮演重覆性的角色 ......... 42
圖七、VPA 會增強細胞內 PI3K/Akt/mTOR 的訊息傳遞 ............................................... 44
圖八、VPA 經由影響 PI3K/Akt/mTOR 的訊息傳遞來減緩 TR2 對 Oct4 promoter 活
性的抑制 .................................................................................................................... 45
圖九、VPA 調控 Oct4 的表現具有階段性的現象，在多能性的細胞中，VPA 會抑制
Oct4 的表現 ............................................................................................................... 46
六、參考文獻 ......................................................... 48

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指導教授

陳盛良(Shen-Liang Chen)

審核日期

2014-7-29

推文