博碩士論文 102224016 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:8 、訪客IP:35.172.233.215
姓名 高健涵(Chien-han Kao)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 E-boxes參與MyoD活化M-cadherin的轉錄 與 Stra13調控PGC-1α的轉錄活化能力
(The involvement of E-boxes in MyoD-mediated M-cadherin activation and the modulation of PGC-1α transactivational ability by Stra13)
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摘要(中) E-boxes參與MyoD活化M-cadherin的轉錄

肌肉調節因子(MRF)家族已被證實,可以透過辨認促進子(E-box)來調控肌肉細胞命運的決定及肌管的形成。 在肌肉發育的過程中,肌肉調節因子透過辨認啟動子上的促進子來活化肌肉相關基因的轉錄。 過去的研究顯示,MyoD可以透過辨認M-cadherin近端啟動子(-252~+200 bp)上的促進子來活化M-cadherin的轉錄。 在M-cadherin近端啟動子上,已知有五個促進子,單一促進子突變的結果顯示,第四號促進子(E-box 4)為M-cadherin啟動子上最為重要的促進子。 因此,對於促進子間的交互作用是否影響MyoD調控M-cadherin的轉錄,仍有待進一步的調查。 最近的實驗結果顯示,除了第四號促進子,第三號促進子(E-box 3)對於MyoD活化M-cadherin的轉錄也十分的重要。 此外,MyoD活化M-cadherin轉錄的效率,可能與啟動子上促進子的數量有關,一旦同時突變超過三個以上的促進子,MyoD活化M-cadherin轉錄的能力將大幅的下降。 實際上,在正常的生理狀態下,MyoD通常會與E47結合,並以二聚體的形式來作用。 因此,為了模擬生理狀態下MyoD的功能,透過一小段具有伸縮性的胺基酸鏈來連結MyoD與E47,以強迫MyoD與E47形成二聚體,此人為修飾的肌肉調節因子MyoD~E47,除了較自然的肌肉調節因子具有更強力的轉錄活化能力之外,還能有效避免細胞內抑制子與MyoD結合。 儘管MyoD~E47相較於MyoD來說,確實可以顯著提升M-cadherin的轉錄效率。 但是MyoD~E47仍無法克服在M-cadherin啟動子上需要三個以上的促進子來完全活化M-cadherin的轉錄。 總結來說,在M-cadherin啟動子上,促進子與MyoD之間確實存著交互作用,但是詳細的調控機制仍有待進一步釐清。




Stra13調控PGC-1α的轉錄活化能力

粒腺體透過進行有氧呼吸來產生高能的三磷酸腺苷(ATP),用以提供無數細胞活動與生存所需的能量。 PGC-1α已被報導可以協同細胞核上的受體(nuclear receptors)來共同調控粒線體的增生與功能。 除了調節粒線體的功能與數量外,PGC-1α也被證實參與了抗氧化及代謝方面的調控。 最近我們實驗室有了一個嶄新的發現,PGC-1α可以與basic helix-loop-helix (bHLH)家族的抑制子Bhlhe40或稱為Stra13產生交互作用。 由於PGC-1α的重要性, Stra13是否會影響PGC-1α所調控的細胞功能是一個值得探討的問題。 實驗結果指出,在Stra13 knockdowned的肌纖維母細胞(C2C12)中, PGC-1α下游基因的轉錄發生了改變。 除此之外,提升的PGC-1α轉錄活化能力,同樣也在Stra13 knockdowned的肌纖維母細胞中被證實。 在生理功能的調控上,Stra13 knockdowned的肌纖維母細胞相較於正常細胞,擁有更多的細胞內自由基(ROS)與減少的粒線體模電位。 增加的氧氣消耗與粒線體數量顯示出,在Stra13 knockdowned的肌纖維母細胞中,粒腺體可能處在一個比較為活躍的狀態。 另一方面,減少的基礎及胰島素誘導的葡萄糖運輸與增加的棕梠酸代謝暗示著,在Stra13 knockdowned的肌纖維母細胞中,細胞對營養利用的偏好可能發生了改變。 就結果來說,Stra13的影響範圍十分廣泛,幾乎影響了全部PGC-1α所參與的調控。 但是,關於這些結果是源於減輕Stra13對PGC-1α的抑制所造成,抑或僅僅只是失去內生性的Stra13所造成的影響,至今尚未十分明瞭,仍有待進一步的釐清。
摘要(英) The involvement of E-boxes in MyoD-mediated M-cadherin activation

The muscle regulatory factor (MRF) family has been known to regulate myogenic cell lineage determination and terminal differentiation of myotubes through targeting consensus enhancer box (E-box). Targeting of MRFs to E-boxes presented in promoter or enhancer region of myogenic genes is important for controlling myogenesis process. According to previous study, MyoD was able to target E-boxes around M-cadherin proximal promoter (-252~+200bp) to activate M-cadherin transcription. There are five defined E-boxes in M-cadherin proximal promoter, and reporter result of single E-box mutation showed that E-box 4 is the most important E-box in M-cadherin promoter. Furthermore, it is of interest to investigate whether the cross-talk between E-boxes and MyoD influences MyoD-mediated M-cadherin activation. Recently, our results showed that besides E-box 4, E-box 3 is also an important E-box for MyoD-mediated M-cadherin activation. Moreover, the efficiency of MyoD transactivating M-cadherin may be related to the E-box number presented in promoter region. Once more than three E-boxes were mutated, the ability of MyoD to transactivate M-cadherin transcription would significantly reduce. Indeed, MyoD prefers to form heterodimer with E47 to function in physical condition. Therefore, the dominant positive myogenic factor, MyoD~E47 tethered protein, was used to mimic physical condition of MyoD function. Although MyoD~E47 tethered protein could significantly enhance M-cadherin transcription when compared to MyoD, but it was unable to overcome that more than three E-boxes were required to fully activate M-cadherin transcription. Taken together, the cross-talk between E-boxes and MyoD is certainly present, but detailed mechanism is still waiting to be clarified.



The modulation of PGC-1α transactivational ability by Stra13

Mitochondria-mediated oxidative respiratory is essential for generating high energy ATP for numerous cellular processes. Peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) had been reported to synergize with several nuclear receptors to control mitochondrial biogenesis and function. Besides mitochondria modulation, PGC-1α had been proved to be involved in anti-oxidation and metabolism modulation. Recently, our lab identified a novel interaction between PGC-1α and basic helix-loop-helix (bHLH) repressor, Bhlhe40 or called Stra13. Due to the importance of PGC-1α, it is of interest to investigate the effect of Stra13 on PGC-1α-regulated cellular processes. Results had indicated that altered expression of PGC-1α targets were observed in Stra13 knockdowned C2C12 cells. Moreover, PGC-1α have showed a better transactivation ability in Stra13 knockdowned C2C12 cells. In physiological modulation respect, Stra13 knockdowned C2C12 cells showed a burst of ROS but a reduced mitochondrial membrane potential. Moreover, increased mitochondria content and oxygen consumption implied that mitochondria in Stra13 knockdowned C2C12 cells is likely to be at a more active state. On the other hand, a regressive basal and insulin-induced glucose uptake but an improved palmitic acid oxidation in Stra13 knockdowned C2C12 cells suggests that a switch of nutrient utilization occurred. Consequently, the effect of Stra13 is extensive, and almost all of PGC-1α-involved regulation have been affected and changed. However, it is still unclear that those observations were resulted from relieving Stra13-mediated PGC-1α functional inhibition or just an unspecific effect of loss endogenous Stra13.

關鍵字(中) ★ 轉錄調控 關鍵字(英) ★ MyoD
★ E-box
★ M-cadherin
★ PGC-1a
★ Stra13
論文目次 中文摘要 7~8
Abstract 9~10
Declaration 11
Acknowledgement 12~13
Table of Contents 13~20
I. Introduction 21~37
Part 1 (The involvement of E-boxes in MyoD-mediated M-cadherin activation) 21~27
I-1-1 Outline
I-1-2 Functional domains of bHLH proteins
I-1-3 Introduction of MRF members
I-1-4 Relationship between E-boxes and MRFs in muscle regulation
I-1-5 Involvement of E-proteins in myogenesis
I-1-6 Id, the negative regulator of MRFs
I-1-7 MyoD~E47 tethered protein, a dominant positive myogenic factor
I-1-8 General introduction of cadherin
I-1-9 Importance of M-cadherin in muscle differentiation
I-1-10 Involvement of M-cadherin in muscle regeneration
Part 2 (The modulation of PGC-1α transactivational ability by Stra13) 28~37
I-2-1 Outline
I-2-2 Discovery of PGC-1α and involvement of it in adaptive thermogenesis
I-2-3 Functions of PGC-1 members in mitochondrial biogenesis
I-2-4 PGC-1 members synergized with nuclear receptors (NRF1, NRF2, ERRα) to prompt mitochondrial biogenesis
I-2-5 PGC-1 members synergized with nuclear receptors (PPARs, ERRα) to regulate nutrient metabolism
I-2-6 Relationship between PGC-1α activity and post-translational modification
I-2-7 Mechanism for Stra13 function
I-2-8 Relationship between PGC-1α and Stra13
II. Materials and Methods 38~64
II-1 Cloning strategies
II-1-1 Restriction enzyme digestion
II-1-2 Polymerase (Taq and Pfu)
II-1-3 klenow
II-1-4 PNK (T4 Polynucleotide Kinase)
II-1-5 Cip (Alkaline Phosphatase, Calf Intestinal)
II-1-6 Ligase
II-1-7 Site directed mutagenesis by overlapping PCR
II-2 Clone list
II-3 Transfection
II-4 Luciferase assay Total protein extraction
II-5 total protein extraction
II-6 Western blot
II-7 RNA extraction
II-8 Reverse transcription-polymerase chain reaction (RT-PCR)
II-9 Quantitative real-time PCR (qRT-PCR)
II-10 shRNA lentiviral production
II-11 shRNA lentiviral infection
II-12 Mechanism for generating a safe lentiviral particle by plasmids
II-13 Reactive oxygen species (ROS) measurement
II-14 Mitochondrial membrane potential (Δψm) measurement
II-15 Intracellular NAD(P)H content measurement
II-16 Genomic DNA extraction
II-17 Mitochondria content determination
II-18 Glucose uptake
II-19 Fatty acid oxidation
II-20 Intracellular ATP content measurement
II-21 Winkler test for dissolved oxygen measurement
II-22 ChIP assay
II-22-1 Step1 (cell harvest)
II-22-2 Step2 (chromatin immunoprecipitation)
II-22-3 Step3 (isolation and purification of genomic DNA fragments)
II-23 Sequential ChIP assay
III. Result 65~98
Part 1 (The involvement of E-boxes in MyoD-mediated M-cadherin activation) 65~70
III-1-1 M-cadherin core promoter with various E-boxes mutation were constructed
III-1-2 E-boxes in M-cadherin core promoter have different importance
III-1-3 E-box 3 is another essential E-box for MyoD-mediated M-cadherin activation
III-1-4 At least three E-boxes are required to fully activate M-cadherin transcription by MyoD
III-1-5 Mimic the physiological condition of MyoD function by MyoD~E47 tethered protein
III-1-6 The activity of M-cadherin promoter is determined by E-box number instead of the intensity of activator
III-1-7 Different myogenic promoter have different competence to regulate the dimerization process between MyoD and E-proteins
III-1-8 M-cadherin core promoter with various E-boxes mutation were constructed
Part 2 (The modulation of PGC-1α transactivational ability by Stra13) 71~98
III-2-1 Monoclone of C2C12-shStra13 was established to investigate the physiological meaning of Stra13 and PGC-1α interaction in skeletal muscle
III-2-2 Expression of potential targets of PGC-1α were investigated by RT-PCR or qRT-PCR in C2C12-shStra13 and control cells
III-2-2-1 Reduced expression of endogenous Stra13 can enhance PGC-1α transcription
III-2-2-2 Stra13 may be involved in the transcriptional control of ETC complex
III-2-2-3 Knockdown of Stra13 does not affect TFAM transcription
III-2-2-4 A switch of nutrient metabolism is observed in C2C12-shStra13 cells
III-2-2-5 A markedly reduced Cat and Sod2 expression are observed in C2C12-shStra13 cells
III-2-2-6 Terminal differentiation markers show a regressive trend in C2C12-shStra13 cells
III-2-2-7 Conclusion of preliminary screening results
III-2-3 Intracellular ROS level was investigated in C2C12-shStra13 cells
III-2-3-1 Reduced expression of endogenous Stra13 leads to a burst of intracellular ROS
III-2-3-2 Mitochondria, the major origin of intracellular ROS, was further investigated
III-2-3-3 Reduced mitochondrial membrane potential but increased mitochondria content in C2C12-shStra13 cells
III-2-3-4 Hypotheses for reduced mitochondrial membrane potential in C2C12-shStra13 cells
III-2-3-5 Reduced mitochondrial membrane potential in C2C12-shStra13 cells is unlikely to be caused by reduction of ETC complexes
III-2-3-6 Intracellular high-energy substrate, NAD(P)H, is sufficient in C2C12-shStra13 cells
III-2-3-7 Reduced mitochondrial membrane potential in C2C12-shStra13 cells may be resulted from activation of uncoupling proteins
III-2-4 Metabolic features were investigated in C2C12-shStra13 cells
III-2-4-1 A reduced basal and insulin-induced glucose uptakes but an improved PA oxidation in C2C12-shStra13 cells
III-2-4-2 More ROS was produced in response to exogenous PA treatment in C2C12-shStra13 cells
III-2-4-3 C2C12-shStra13 cells prefer and are more efficient to utilize fatty acid (PA) as energy resource instead of glucose
III-2-4-4 Increased oxygen consumption in Stra13 knockdowned C2C12 cells
III-2-4-5 Exogenous PA treatment reduces the oxygen consumption in C2C12-shStra13 cells
III-2-4-6 Stra13 is an essential factor for modulating peroxisome content in C2C12 cells
III-2-5 Stra13-mediated PGC-1α functional inhibition is partly realized by recruiting histone deacetylase (HDACs) to promoter region
III-2-6 Improved PGC-1α expression at both mRNA and protein level in mice performed oxidative training
III-2-7 Truncated Stra13 fragment (1~135) blocks Stra13-mediated inhibition on potential PGC-1α targets
III-2-8 Reduced mitochondria content and intracellular ATP content in VP16-Stra13 1~135 overexpressed C2C12 cells
III-2-9 Stra13 can interact with PGC-1α in vivo
III-2-10 Establishment of Tet-off system based Stra13 overexpressed C2C12 cells
III-2-11 Effects of Stra13 overexpression on PGC-1α-mediated gene regulation and cellular processes
IV. Discussion 99~110
Part 1 (The involvement of E-boxes in MyoD-mediated M-cadherin activation) 99~102
Part 2 (The modulation of PGC-1α transactivational ability by Stra13). 103~110
V. Reference 111~118
VI. Figures 119~149
Figure. 1. Cross-talk between E-boxes and MyoD in M-cadherin core promoter
Figure. 2. The dominant positive myogenic factor, MyoD~E47 tethered protein, is not enough to fully activate M-cadherin core promoter retaining only E-box 3 and 4, two of the most important E-boxes
Figure. 3. Establishment of Stra13 knockdowned C2C12 cells through shRNA
Figure. 4. Effects of Stra13 knockdown on mRNA expression of potential PGC-1α targets
Figure. 5. Intracellular ROS level and mitochondrial membrane potential were determined in C2C12-shStra13 and control cells
Figure. 6. Higher mtDNA/ncDNA ratio and intracellular NAD(P)H in Stra13 knockdowned C2C12 cells
Figure. 7. Altered preference of nutrient utilization occurred in Stra13 knockdowned C2C12 cells
Figure. 8. General ATP production and oxygen consumption were determined in C2C12-shStra13 and control cells in the present or absent of fatty acid supply
Figure. 9. Stra13 is essential for modulating peroxisome content in C2C12 cells
Figure. 10. Involvement of HDACs in Stra13-mediated PGC-1α inhibition
Figure. 11. Mice performed oxidative training show an enhanced expression of PGC-1α and its targets
Figure. 12. Overexpressing truncated Stra13 fragment with VP16 modification is efficient to improve PGC-1α function and its targeted genes expression
Figure. 13. Stra13 can interact with PGC-1α in vivo
Figure. 14. Effects of Stra13 overexpression on transcription of potential PGC-1α targets and other PGC-1α-regulated cellular processes
VII. Appendixes 150~160
VII-1 Solutions
VII-2 Primer list
VII-3 Other Clone list
VII-4 Equilibrium equation and experimental steps of Winkler test
VII-5 Scheme of mutagenesis by overlapping PCR
VII-6 Outstanding poster award in the Twenty-third Symposium on Recent Advances
in Cellular and Molecular Biology

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指導教授 陳盛良(Shen-liang Chen) 審核日期 2015-6-17
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