MyoD對於PGC-1α 基因表現之調控機制

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張如慧(Ju-Hui Chang) 查詢紙本館藏

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生命科學系

論文名稱

MyoD對於PGC-1α 基因表現之調控機制
(The mechanism of PGC-1α gene expression regulated by MyoD)

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摘要(中)

MRF (Myogenic Regulatory Factor)家族中basic Helix-Loop-Helix轉錄因子-MyoD、Myf-5、Myogenin以及MRF-4，為肌肉細胞品系的決定者，而它們也是調控肌肉細胞末期分化的主要因子。若將MRF家族的其中一員於非肌肉細胞中過度表現時，則會使得這些細胞轉變成肌肉細胞。然而肌肉細胞要轉變為成熟的肌肉細胞，則還須有MEF-2 (Myocyte Enhancer Factor-2)的參與。MEF-2和肌肉生成之bHLH蛋白會以形成異行雙聚物的方式去調控肌肉特化基因的表現進而促進肌肉細胞的成熟。而另一轉錄因子FKHR (Forkhead in Rhabdormyosarcoma)在肌肉末期分化上也扮演著相同的重要角色，它會促進肌纖維母細胞間的融合，此為肌肉細胞分化的必要過程。最近的研究指出，MEF-2和FKHR皆會調控PGC-1α (Peroxisome proliferator-activated receptor (PPAR)-γ Coactivator-1)的表現，而PGC-1α是調控慢收縮肌纖維形成的重要因子。既然MEF-2 和 FKHR 這這兩者都會影響肌肉之末期分化，因此引發我們進一步去研究，肌肉中是否有其他肌肉特有轉錄因子，例如MyoD或其同一家族的其他成員是否也會調控PGC-1α。本篇主要是針對肌肉細胞品系決定的調節者MyoD (myogenic determination factor) 進行研究。在本篇研究中，我們發現 PGC-1 α 核心驅動子上之兩個 E-box在MyoD之作用上扮演著極關鍵的角色。將這兩個E-box其中之一突變後，都會明顯減少經由MyoD 所誘發之PGC-1 α 核心驅動子之轉錄活性。此外，我們也發現當肌纖維母細胞分化成肌管(myotube)時，PGC-1α的表現也隨之增加。而根據我們以反轉錄病毒方法所製備之MyoD穩定表達細胞株也發現，當其分化成肌管時，PGC-1α的表現同樣也會隨之增加。因為 PGC-1α被認為是決定肌纖維種類之主要調控者，我們的結果顯示MyoD不僅是和肌肉品系的決定以及末期分化有關，它也可能會影響成熟肌肉細胞的肌纖維種類以及代謝方式的轉換。

摘要(英)

Determination of myogenic lineage is dictated by the function of bHLH transcription factors of MRF (Myogenic Regulatory Factor) family, which consists of MyoD, Myogenin, Myf-5 and MRF-4, and they are also the major factors regulating terminal differentiation of muscle cells. Overexpression of any one of the MRF family in several non-myogenic cells can induce their trans-differentiation into myogenic lineage. However, myoblsts differentiate into mature muscle cells still need the help of MEF-2 (Myocyte Enhancer Factor-2). MEF-2 proteins can cooperate with myogenic bHLH proteins as a heterodimer to regulate the expression of muscle-specific genes and commit myoblasts to terminal differentiation. Another factor, FKHR, also plays a role in terminal differentiation by promoting the fusion of myoblasts which is the essential process of myoblasts differentiation. Recently, PGC-1α (Peroxisome proliferator-activated receptor PPAR-γ Coactivator-1α) was shown to promote the formation of slow-twitch fibers, and which is regulated by MEF2 and FKHR. Since MEF-2 and FKHR are both implicated in the terminal muscle differentiation, it prompts us to study the regulation of PGC-1α in muscle by other muscle-specific transcription factors, such as MyoD and its family members. Here we show that MyoD can activate PGC-1α expression by binding to two putative E-boxes localized to its core promoter. Mutation of either site significantly reduced MyoD mediated transactivation. We also found out that when myoblast differentiates into myotube the expression of PGC-1α is up-regulated. The expression of PGC-1α also increased in retrovirus-mediated MyoD-overexpressed cells when they differentiate into myotubes. Since PGC-1α is suggested to be the principle factor regulating muscle fiber type determination, our results indicate that MyoD is not only involved in the lineage determination and terminal differentiation, but may also implicated in the fiber-type and metabolic switch of mature muscle cells.

關鍵字(中)

★ 肌肉

關鍵字(英)

★ MyoD
★ PGC-1

論文目次

目錄
中文摘要………………………………………………………….......І
Abstract………………………………………………………….......Ⅱ
目錄………………………………………………………………….Ш
圖目錄……………………………………………………………….Χ
縮寫與全名對照表………………………………………………......ⅩⅡ
第一章、緒論
I. 肌肉的起源……………………..……….……...……………..1
II. MyoD在肌肉細胞的功能………………..……………….....1
III. PGC-1α的功能……………………………………………..4
IV. 研究動機與目的…………..………………………………...5
第二章、材料與方法
І.實驗材料
1. 細胞株
1.1細胞培養…………………………………………….……..7
2. 菌株
2.1菌株培養…………………………………………………….7
2.2菌株的保存………………………………………………….7
Ⅱ. PGC-1α-Luc 報告質體(reporter plasmid)之構築
1. pRL-hPGC-1α報告質體的次選殖(subclone)
1.1 大腸桿菌勝任細胞之製備（Preparation of E. coli
competent cells)………………………………………...8
1.2 大腸桿菌的轉型作用 (Transformation)………………....8 1.3 質體DNA 的少量製備 (Mini-preparation) – 用鹼處理法 (Alkaline lysis method) ：
1.4 篩選 (Screening)
1.4.1 核酸限制酶的剪切:……………………………………9
1.5 插入DNA (PGC-1α)的製備……………………………..10
1.5.1限制酶的剪切………………………………………10
1.5.2插入(Insert)DNA的純化……………………………10
1.6 載體DNA (pGL3 basic)的製備…………………………10
1.7 載體DNA (pGL3 basic)的5’端去磷酸根反應………….11
1.7.1限制酶的剪切………………………………………11
1.7.2載體DNA (pGL3 basic)的5’端去磷酸根反應…….11
1.8 接合反應 ( Ligation )……………………………………12
1.9篩選 (Screening)………………………………………….12
1.9.1質體DNA 的少量製備 (Mini-preparation) –
用鹼處理法(Alkaline lysis method) :……………………..12
1.9.2核酸限制酶剪切…………………………………………12
1.10 核酸定序(DNA sequencing)…………………………....12
2. PGC-1α promoter 較短片段的製備
2.1 限制酶的剪切…………………………………………….12
2.1.1 pGL3-hPGC-1α (-630 ~ +90)-Luc…………………..12
2.1.2 pGL3-hPGC-1α (-444 ~ +90)-Luc…………………..13
2.1.3 pGL3-hPGC-1α (-992 ~ -444)-Luc………………….13
2.1.4 pGL3-hPGC-1α (-676 ~ +90)-Luc…………………..13
2.2 接合反應 ( Ligation )…………………………………….14
2.3 篩選 (Screening)…………………………………………14
2.3.1質體DNA 的少量製備 (Mini-preparation) –
用鹼處理法(Alkaline lysis method) ：…………………...14
2.3.2核酸限制酶剪切…………………………………….14
3. PGC-1α promoter (-233 ~ +19)野生型片段的製備
3.1 引子的設計………………………………………………14
3.2 聚合酶鏈反應 (Polymerase Chain Reaction, PCR)……..15
3.3 聚合酶鏈反應產物的修飾………………………………..15
3.4 載體DNA (pGL3 basic)的5’端去磷酸根反應…………...16
3.4.1限制酶的剪切………………………………………..16
3.4.2載體DNA (pGL3 basic)的5’端去磷酸根反應………16
3.5 聚合酶鏈反應篩選 (PCR screening)…………………....16
4. PGC-1α core promoter 突變型片段的製備
4.1 引子的設計……………………………………………...16
4.2 模板DNA的合成………………………………………17
4.3 聚合酶鏈反應 (Polymerase Chain Reaction, PCR)……17
4.4 聚合酶鏈反應產物的修飾……………………………...18
4.4.1聚合酶鏈反應產物的分析…………………………18
4.4.2聚合酶鏈反應產物的修飾…………………………18
4.5 接合反應 ( Ligation )…………………………………..18
Ⅲ. PGC-1α promoter 於哺乳類細胞中之活性
1. 質體pGL3-hPGC-1α的轉染 (Transfection)
1.1 細胞培養…………………………………………….18
1.2 轉染作用…………………………………………….19
1.3 螢火蟲冷光活性方法……………………………….19
Ⅳ. PGC-1α promoter與核蛋白質之相互作用
1. 電泳速度變動分析法 (Electrophoresis Mobility Shift
Assay, EMSA)
1.1 核蛋白的萃取……………………………………….20
1.2 蛋白質的定量……………………………………….20
1.3 探針 (Probe)的製備………………………………...20
(1) 引子的設計:…………………………………….20
(2) 聚合酶鏈反應：………………………………………21
1.4 探針的標定(Labeling)…………………………………….21
1.5 探針的純化……………………………………………….21
1.5.1聚丙烯醯胺膠體分離法 (PAGE Separation)………21
1.5.2 DNA位於膠體上位置之辨認 (Band Recognition)..21
1.5.3 DNA的收集………………………………………...22
1.6 結合分析法 (Binding assay)……………………….........22
Ⅴ. pMSCV-neo-mMyoD表現載體之構築
1. 載體DNA ( pMSCV neo ) 的製備………………………..23
2. 插入DNA ( MyoD )的製備……………………………….23
3. 接合反應 ( Ligation )……………………………………..23
4. 篩選 ( Screening )…………………………………………23
Ⅵ. 利用反轉錄病毒( Retrovirus )將MyoD基因表現於哺乳類細胞中
1. 反轉錄病毒的製備：
1.1 細胞培養………………………………………………24
1.2 轉染作用………………………………………………24
2. 利用反轉錄聚合酶鏈反應( RT-PCR )篩選反轉錄病毒製備成功
2.1 Total RNA的抽取……………………………………..24
2.2 反轉錄酶反應(Reverse Transcriptase, RT)………...25
2.3 聚合酶鏈反應( Polymerase Chain Reaction, PCR )..25
3. 質體pMSCV-neo-MyoD的感染(Infection)
3.1 細胞培養……………………………………………..26
3.2 感染作用……………………………………………..26
4. 利用反轉錄聚合酶鏈反應篩選MyoD穩定表達細胞株
4.1 Total RNA的抽取…………………………………..26
4.2 反轉錄酶反應(Reverse Transcriptase, RT)………...26
4.3 聚合酶鏈反應( Polymerase Chain Reaction, PCR ).26
5. 利用西方點墨法(Immunoblotting)偵測MyoD之表現..27
Ⅶ.即時定量聚合酶鏈反應( Real- Time PCR )…………….27
Ⅷ. 利用反轉錄聚合酶鏈反應判別肌纖維種類……………27
第三章、結果……………………………………………….29
第四章、討論………………………………………...….….37
第五章、參考文獻…………………………………...……57
反轉錄病毒的製備流程………………………………61
附錄一……………………………………………..…………62
附錄二……………………………………………..…………66
附錄三……………………………………………..…………67
附錄四……………………………………………..…………69
圖目錄
圖一、轉錄因子對於PGC-1α promoter活性的影響
………………………………………………………...............40
圖二、不同濃度的MyoD對於PGC-1α promoter活性
之影響…………………………………………………………41
圖三、以自體接合製備較短的PGC-1α promoter片段
………………………………………………………………..42
圖四、 MyoD之轉錄活性對於PGC-1α promoter之調控是必要的……………………………………………………………...43
圖五、以聚合酶鏈反應篩選PGC-1α promoter ( -233~+90 )區間之
質體……………………………………………………………44
圖六、 MyoD對於PGC-1α promoter -233 ~+90區間活性的影響
………………………………………………………………45
圖七、 MRF家族轉錄因子對於PGC-1α core promoter活性的影響
……………………………………………………………….46
圖八、以聚合酶鏈反應篩選突變型PGC-1α core promoter質體
……………………………………………………………….47
圖九、MyoD對於突變型PGC-1α core promoter活性的影響
…..……………………………………………………………48
圖十、探討MyoD蛋白質和PGC-1α promoter之間的作用關係
….…………………………………………….......................49
圖十一、MyoD 反轉錄病毒之建立流程圖
………………………………………………………………50
圖十二、 MyoD穩定表達細胞株之建立流程及確認圖
…………………………………………………………..51
圖十三、 MyoD穩定表達細胞株之形態圖
………………………………………………………….52
圖十四、 MyoD穩定表達細胞株對於PGC-1基因表現的影響…………………………………………….................53
圖十五、 PGC-1基因在肌纖維母細胞中的表現…………….....55
圖十六、纖維種類指標基因(fiber-type marker genes)在MyoD
穩定表達細胞株之表現情形………….........................56

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指導教授

陳盛良(Shen-Liang Chen)

審核日期

2005-4-13

推文