探討丙戊酸 (Valproic acid) 活化 Sox2 和 Oct4 promoter 的機制

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林政道(Cheng-Tao Lin) 查詢紙本館藏

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論文名稱

探討丙戊酸 (Valproic acid) 活化 Sox2 和 Oct4 promoter 的機制
(The mechanism of valproic acid enhanced Sox2 and Oct4 promoter activation)

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摘要(中)

在 2006 年，Takahashi and Yamanaka 藉由在細胞內大量表現 Oct4, Sox2, Klf4 及 c-Myc 成功將老鼠胚胎纖維母細胞誘導成具有多能性的幹細胞 (iPS cells)。而近年研究指出 DNA methyltransferase and histone deacetylase (HDAC) inhibitors 等許多小分子化合物，可有效提升 re-programming 的效率，且有研究指出藉由加入 HDAC inhibitor: Valproic acid (VPA)，可以成功的在只有大量表現 Oct4, Sox2 的情況下，產生多能性的幹細胞。因此我們的研究集中在 VPA 這個 HDAC 的抑制劑，在我們的研究當中發現 VPA 能夠在C2C12 細胞中提升 Oct4基因的表現並增強 Oct4 1.9k promoter 的活性；在 P19E 細胞中能提升 Sox2 基因的表現，但在 Neuro-2a 和 C2C12 中則不行。但 Sox2 promoter 的活性卻可以在 P19E 及 C2C12 細胞中被活化。並發現在大量表現 TR2 及 PPARδ 的情況下，可以增強 VPA 活化 Oct4 promoter 的活性，表示 TR2 及 PPARδ 可能為 VPA 調控 Oct4 promoter 主要的因子。而 VPA 對 Sox2 promoter 主要的作用位置在-2169~-2111 的區域，此區域具有 Tal1 的 binding site。利用突變 Tal1 binding site 及 Tal1 knockdown，確實可以大幅降低 Sox2 promoter 對 VPA 的反應，證實 Tal1 對 VPA 活化 Sox2 promoter 的機制扮演重要的角色。此外處理各種訊息傳遞抑制劑後，發現 LY294002 (Akt inhibitor) 及 rapamycin (mTOR inhibitor) 可以抑制 VPA 活化 Sox2 promoter 的活性，且 VPA 可以活化細胞內的 Akt 和 mTOR，顯示 VPA 可能藉由活化 PI3K/Akt/mTOR pathway 來活化 Sox2 及 Oct4 的 promoter。而未來將會探討 Tal1 是否會結合在 Sox2 promoter -2169~-2111 的區域，以及瞭解 VPA 經由 PI3K/Akt/mTOR 訊息傳導路徑來影響 Sox2 promoter 活性的機制。

摘要(英)

In 2006, Takahashi and Yamanaka reprogrammed mouse embryonic fibroblasts to induced pulripotent stem cells (iPSC) by over-expressing Oct4, Sox2, Klf4 and c-Myc. In recent study, DNA methyltransferase and histone deacetylase (HDAC) inhibitors are found to improve reprogramming efficiency. And they treated valproic acid (VPA), a histone deacetylase inhibitor, to enables reprogramming of primary human fibroblasts with only two factors, Oct4 and Sox2. In this study we found VPA could enhance both the Oct4 1.9k promoter activity and Oct4 expression in C2C12. And VPA could enhance Sox2 expression in P19 cells but not in C2C12 or Neura2A cells. However, Sox2 promoter activity was induced by VPA in both C2C12 and P19 cells. In order to search for major nuclear receptor mediating VPA enhanced Oct4 promoter activation, we found that overexpressing TR2 and PPARδ could enhance the ability of VPA activate Oct4 promoter. VPA response element on Sox2 promoter was localized to the upstream region between -2169 and -2111 bp. Mutation of the Tal1-binding site in this region and Tal1 knockdown largely reduced its VPA response, implying that this binding site plays important role in this response. In addition, we found LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor) could reduce VPA induced Sox2 promoter activity, implying that VPA may activate Oct4 and Sox2 promoters by activating PI3K/Akt/mTOR pathway. In the future, we will define whether Tal1 could directly bind to Sox2 promoter -2169~-2111 region and the mechanism by which VPA activate Sox2 promoter via PI3K/Akt/mTOR signal pathway.

關鍵字(中)

★ 丙戊酸

關鍵字(英)

★ Valproic acid
★ Sox2
★ Oct4

論文目次

目錄
中文摘要 V
Abstract VI
誌謝 VII
一、緒論 1
一、胚胎發育 (embryogenesis) 1
二、誘導型多能性幹細胞 (Induced pluripotent stem cells, iPS) 2
三、Valproic acid 5
四、Oct4 與 Sox2 8
五、研究動機與目的 12
二、材料與方法 13
2-1質體的建構 13
插入 (Insert) DNA 的純化 16
載體 (Vector) DNA 的純化 16
接合反應 ( Ligation ) 16
大腸桿菌的轉型作用 (Transformation) 16
2-2細胞株 17
2-3 RT-PCR 17
2-3 Real-time PCR 19
2-4 Transient promoter assay 啟動子轉染分析 19
2-5 西方墨點實驗 (Western blot) 19
2-6 藥物配製 21
三、實驗結果 22
3-1 觀察 Neuro-2a、P19E、C2C12 細胞株內，經 VPA 處理後 Sox2 基因表現情形 22
3-2 探討 VPA 作用於 Sox2 promoter 的位置 22
3-3 探討移除 -2169~-2111 區域後，Sox2 promoter對 VPA 的反應 23
3-4 Sox2 promoter -2629~-1951 的區域具有哪些 transcription factor binding site 23
3-5 T-cell acute lymphocytic leukemia 1 (Tal1) 是否影響 VPA 增強 Sox2 promoter 的轉錄活性 24
3-6 Msx1、GATA-1、Mzf1、Alx1及Hltf 是否參與 VPA 增強Sox2 promoter 轉錄活性的機制中 25
3-7 SF1、TR2、TR4、ER、Nurr-1、Nor-1及RARα 是否參與 VPA 增強Oct4 promoter 轉錄活性的機制中 26
3-8 TR2 knock down 後是否影響 VPA 活化 Oct4 promoter 轉錄活性 27
3-9 PPARδ 是否參與 VPA 增強Oct4 promoter 轉錄活性的機制中 27
3-10 探討 VPA 經由哪個訊息傳導路徑來增強 Sox2 promoter 的轉錄活性 28
3-11 VPA 是否會活化 C2C12 細胞中的 Akt 及 mTOR 28
四、實驗討論 30
4-1 VPA 與 Oct4、Sox2的關係 30
4-2 VPA 作用在 Oct4 和 Sox2 promoter的位置 31
4-3 VPA 活化Sox2 promoter 的訊息傳導路徑 32
五、參考文獻 35
六、圖表 42
圖一、 Neuro-2a、P19E、C2C12 細胞經 VPA 處理後， Sox2 基因表現情形 42
圖二、VPA 於 C2C12 細胞中，對不同片段 Sox2 promoter 的影響 44
圖三、在 Sox2 promoter -2169~-2111 deletion 後，對 VPA 的反應 45
圖四、在 Sox2 promoter 上，有哪些 transcription binding site 46
圖五、在 Sox2 promoter Tal1 binding site mutation 後，對 VPA 的反應 48
圖六、VPA 增強 Sox2 promoter 的活性，是否會受到 Msx1、Gata-1、Mzf1、Alx1及Hltf 的影響 52
圖七、VPA 增強 Oct4 promoter 的活性，是否會受到 SF1、TR2、TR4、ER、Nurr-1、Nor-1及RARα的影響 55
圖八、將 TR2 knock-down 後，VPA 增強 Oct4 promoter 的活性是否會受到影響 56
圖九、VPA 增強 Oct4 promoter 的活性，是否會受到 PPARδ的影響 58
圖十、C2C12 細胞處理 signal pathway inhibitor 後，VPA 活化 Sox2 promoter 的情形 59
圖十一、C2C12 細胞處理 VPA 後，Akt 及 mTOR 活化的情形 61
附錄一 62
圖一、 C2C12-Retro-Py-GFP 及 C2C12-Oct4-Py-Nanog-Sox2 經 VPA 處理後其幹細胞及肌肉分化相關基因表現情形 63
圖二、 VPA 在 P19E 及 C2C12 細胞中對 Sox2 promoter 活性的影響 64
圖三、 VPA 於 C2C12 細胞中，對不同片段 Sox2 promoter 的影響 65
圖四、 VPA 對於不同長度 Oct4 promoter 的影響 67
附錄二 68
附錄三 71
1. Primer 對照表 71
2. 縮寫與全名對照表 72
3. 溶劑及試劑配方 73

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指導教授

陳盛良(Shen-Liang Chen)

審核日期

2012-8-17

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