探討纖維母細胞生長因子在肌原細胞中對MyoD基因表達的調節

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研究生：	范舒馨 Shu-Hsin Fan
論文名稱：	探討纖維母細胞生長因子在肌原細胞中對MyoD基因表達的調節 The regulation of MyoD expression by basic fibroblast growth factor in myoblasts
指導教授：	陳盛良 Shen-Liang Chen
口試委員:
學位類別：	碩士 Master
系所名稱：	生醫理工學院 - 生命科學系 Department of Life Science
論文出版年：	2020
畢業學年度：	108
語文別：	中文
論文頁數：	125
中文關鍵詞：	骨骼肌肉細胞、肌原細胞、肌原細胞決定因子、纖維母細胞生長因子、Wnt3a 、肌肉分化過程、啟動子、轉錄因子
外文關鍵詞：	skeletal muscle, myoblasts, MyoD, bFGF, Wnt3a, myogenesis, promoter, transcription factor
相關次數：	點閱：7 下載：0
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中文摘要
在脊椎動物中，軀幹體節(somite)的發育會受到周圍生長因子的影響。位於體節dermomyotome中的幹細胞受到從細胞外基質和神經管底層釋放的肌肉生成因子的影響，會走向表現Pax3和Pax7的肌肉幹細胞 (myogenic stem cells, MSC)。之後，MSC細胞中的肌肉專一性調節因子(Muscle Regulatory Factors, MRFs) MyoD及Myf5的表現被誘發後，可活化下游與肌肉分化有關的基因表現，使MSC成為肌原母細胞 (myoblasts)。由於MyoD可以促使幹細胞走向肌肉發育，因此被稱為肌肉生成的主要調節因子。目前有文獻已知在體節附近分泌的纖維細胞生長因子 (bFGF)會響肌肉發育的過程，但是它對MyoD表達的影響仍然值得探討。本研究主要透過實驗室建立的MyoD promoter以及其上游的片段 (cis-element, -20~-6 kb)，分析bFGF在肌肉分化過程中潛在的調控機制。我們的結果顯示經由處理bFGF的myoblasts，其MyoD表現量會被抑制且提高Pax3與Myf5的表現量，並促進細胞增生。透過分段測試MyoD promoter上游的cis-element，發現bFGF會藉由C片段 (-18 ~ -17kb)、G片段 (-14~ -13kb)、M片段 (-8 ~ -7kb) 影響MyoD promoter的活性，我們推測這些片段可能有影響MyoD promoter活性的轉錄因子結合區域。經由生物資訊軟體分析預測，篩選出AP1、AP4及Sox5為潛在的可受到bFGF影響而調控MyoD表現的轉錄因子。bFGF也透過活化MAPK (JNK, p38和Erk)與Akt訊息傳遞路徑調控AP1、AP4及Sox5的表現，之後的研究可以再探討潛在的轉錄因子與MyoD之間的調控關係。同時也發現bFGF雖然抑制MyoD promoter活性，但卻不影響MyoD調控下游的基因功能，所以bFGF應該不會干擾MyoD的正向自我活化。此外，我們也探討了Wnt3a和bFGF之間的關係，因為這兩種因子都對肌肉幹細胞生成和MyoD表達有很重要的影響。實驗結果顯示Wnt3a和bFGF同時存在對胚胎和成體肌肉細胞的肌肉發育信號的影響是一致，它們皆誘導Pax3、Myf5的表現去維持肌原細胞的特異性，並具有共同促進肌肉細胞再生及分化的功能。綜合以上結果，證明bFGF是透過多方面的信號傳遞途徑調控MyoD上游的轉錄因子，而這些不同的轉錄因子會結合在MyoD上游不同的cis-elements上，抑制MyoD的表現。

Abstract
In response to local myogenic signals transmitted from their surrounding tissues, some stem cells in dermomyotome of somites will become Pax3- and Pax7- expressing myogenic stem cells (MSC). These stem cells will be further confined within the myogenic lineage by the expression of muscle-specific transcription factors, either MyoD or Myf5 that will activate their downstream transcription factors and other muscle-specific genes to drive MSC to become myoblasts. MyoD is called as the master regulator of myogenesis and it can turn on the whole myogenic program in MSC or cells of other lineages, so induction of MyoD expression leads to determination and development of myogenic cells. A few signals found in the somite neighborhood, such as basic fibroblast growth factor (bFGF), released from extracellular matrix and the floor plate of neural tube have been found to promote myogenic program but their effects on MyoD expression has not been analyzed thoroughly. In this study, the MyoD-reporters driven by MyoD promoter and its upstream fragment (-20 ~ -6 kb) were used to analyze the potential regulatory mechanism of bFGF during muscle differentiation. Our results showed that myoblasts treated with bFGF not only inhibited the expression of MyoD but also increased the expression of Pax3 and Myf5 and promoted cell proliferation. Through screening a series of genomic fragments upstream of MyoD promoter, we found that bFGF affected the activity of MyoD promoter through the C fragment (-18~-17kb), G fragment (-14~-13kb) and M fragment (-8~-7kb). Based on the analysis and prediction of bioinformatics software, AP1, AP4, and Sox5 were identified as potential transcription factors that might be induced by bFGF to regulate MyoD expression. Later studies should explore the regulatory relationship between these potential transcription factors and MyoD. We also found that bFGF could activate MAPK (JNK, p38 and Erk) and Akt signaling pathways to trigger downstream gene expression. At the same time, we also found that although bFGF does not affect the transactivational activity of MyoD, implying that FGF does not interfere with the positive feedback loop of MyoD. In addition, we also explore the cooperation between Wnt3a and bFGF, because they have important effects on muscle stem cell proliferation and MyoD expression. We found the same effects in embryo and adult muscle cells that they both induce the expression of Pax3 and Myf5 to maintain the myogenic cell lineage and have the function of promoting muscle cell regeneration and differentiation. Based on the above results, it is proved that bFGF regulates the transcription factors upstream of MyoD through various signal transduction pathways, and these different transcription factors will bind to different cis-elements upstream of MyoD to inhibit its expression.

目錄 (Table of Contents)
中文摘要    i 
Abstract    ii 
聲明 Declaration    iii 
誌謝 Acknowledgement    iv 
縮寫 Abbreviations    v 
目錄 Table of Contents    vi 

一、簡介 Introduction    1
I. 肌原細胞 (Myoblast)    1
II. MRFs (Muscle Regulatory Factors)家族    2
III. MyoD對於骨骼肌肉發育的重要性(The importance of MyoD for skeletal muscle development)    2
IV. 纖維母細胞生長因子(basic fibroblast growth factor, bFGF)    3
V. 肌肉衛星細胞（Satellite cell）    4
VI. Wnt3a與肌肉發育之關係(Wnt3a and muscle development)    5
VII. 研究動機與目的 (Research motivation and purpose)    5
二、實驗材料與方法Materials and Methods    6
2-1 細胞株 (cell lines)    6
2-1-1穩定表現細胞株 (stable clone)    6
2-1-2 FVB老鼠胚胎的初代培養 (Mouse embryo primary culture)    7
2-2質體構築Cloning    7
2-2-1 質體 (plasmids)    7
2-2-2 菌株 (bacterium)    10
2-2-3 聚合酶鏈鎖反應 (Polymerase Chain Reaction ,PCR)    10
2-2-4 Insert DNA的純化    12
2-2-5 Vector 5’去磷酸根反應(Calf Intestinal Alkaline Phosphatase, C.I.P)    12
2-2-6 Klenow (DNA polymerase I, Large Fragment)    13
2-2-7接合反應 (Ligation)    13
2-2-8 大腸桿菌的轉型作用 (Transformation)    14
2-3 RT-PCR    14
2-3-1 Total RNA 製備：    14
2-3-2 反轉錄酶反應 (Reverse Transcriptase, RT)    14
2-4  Real Time PCR 定量實驗    15
2-5 細胞轉染作用 (Cell Transfection)    16
2-5-1 螢火蟲冷光活性方法 (Luciferase Activity Assay)    16
2-5-2 測protein 濃度及normalize方法    17
2-6 蛋白質表現及純化 (Protein expression and purification)    17
2-7 西方墨點實驗 (Western blot)    20
2-8 免疫染色 (Immunohistochemistry)    21
2-9 流式細胞儀分析技術(Flow Cytometric Analysis of Cell Cycle)    22
2-10 染色質免疫沉澱(ChIP, Chromatin immunoprecipitation assay)    24
三、實驗結果Results    27
3-1純化GST和bFGF recombination protein    27
3-2 確認純化的GST-bFGF protein是否具有促進細胞增生的功能    27
3-3 確認GST-bFGF protein是否會影響C2C12細胞分化    28
3-4 分別以10% FBS和5% HS兩種不同的medium 測試GST-bFGF對MyoD的影響是否相同    29
3-5 GST-bFGF透過AKT, MAPK signal pathway調控MyoD和其下游基因    29
3-6 探討GST-bFGF影響MyoD promoter cis-elements上哪些片段及預測相關的轉錄因子    30
3-7 觀察C2C12細胞從CMB到MT stage的過程中哪些基因的表現受到GST-bFGF影響    31
3-8 觀察在胚胎中哪些基因受到GST-bFGF影響    33
3-9 GST-bFGF是否也抑制了MyoD transactivity的能力導致大幅降低MyoG(Myogenin) promoter 轉錄活性    33
3-10 GST-bFGF和Wnt3a之間的interaction會影響C2C12細胞中哪些基因    34
3-11 GST-bFGF和Wnt3a之間的interaction會影響胚胎中哪些基因    35
四、實驗討論Discussion    36
4-1 GST-bFGF recombination protein的純化條件與其功能的確認    36
4-2 GST-bFGF可能會影響肌肉細胞的cell lineage    37
4-3 GST-bFGF和Wnt3a之間的interaction可能幫助肌肉細胞分化    37
4-4 GST-bFGF可能透過調控AP1或SOX5間接影響MyoD的基因表現    38
4-5 結論Conclusion    39
五、參考文獻References    40
六、圖表Figures    49
Fig.1純化GST和GST-bFGF蛋白    49
Fig.2純化的GST-bFGF對C2C12細胞生長的影響    53
Fig.3 GST-bFGF對C2C12細胞分化的影響    57
Fig.4測試GST-bFGF在10% FBS和5% HS培養液中對MyoD的影響    59
Fig.5探討GST-bFGF影響肌肉細胞分化相關基因表現及訊息傳遞路徑    60
Fig.6探討GST-bFGF對MyoD promoter cis-elements活性的影響    63
Fig.7觀察GST-bFGF對肌肉細胞從未分化到分化過程中基因表現的影響    72
Fig.8觀察GST-bFGF對老鼠胚胎肌肉發育的基因表現量之影響    76
Fig.9 GST-bFGF對MyoD transactivity的影響    78
Fig.10探討GST-bFGF和Wnt3a共同影響肌肉分化過程中的重要基因    79
Fig.11觀察GST-bFGF和Wnt3a同時存在會影響胚胎肌肉發育的哪些基因    84
Fig.12推測GST-bFGF可能會影響肌肉細胞的 cell lineage    86
Fig.13推測GST-bFGF和Wnt3a可能會共同促進肌肉細胞再生和分化    86
Fig.14 GST-bFGF可能調控AP1、AP4和Sox5竟而影響 MyoD的表現    87
附錄一    88
Supplementary figure1 從決定肌肉細胞命運到細胞分化的過程    88
Supplementary figure 2影響體節分化的主要旁分泌訊號    88
Supplementary figure 3肌肉發育過程中MRFs signal 分布    89
Supplementary figure 4 MyoD promoter和enhancer的重要活性部分    90
Supplementary figure 5 General growth factors signaling pathway    91
Supplementary figure 6 FGF2 signaling pathway    92
Supplementary figure 7 Satellite cell marker    93
附錄二    94
Supplementary figure 8 設計ChIP Assay實驗C、G、M片段中AP1、Sox5 binding site的primer    94
Supplementary figure 9探討低濃度的GST-bFGF和Wnt3a對C2C12 細胞的影響    95
Supplementary10 bFGF的蛋白質、DNA和胺基酸序列補充資訊    96
Supplementary11老鼠懷孕周期 (Mouse pregnancy cycle)    98
Supplementary12胚胎發育 (Embryogenesis)    99
附錄三    102
Primer 對照表    102
Clone 對照表    106
附錄四    107
抗體    107
溶液及試劑配方    108


                                

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