Abstract
摘要:ATP 合成酶是由DNA解旋酶和氫離子馬達結合,藉由氫離子梯度使馬達旋轉,而驅動ATP合成,這樣的旋轉機制在演化過程中效率漸增。因為ATP合成酶是一個古老的蛋白質,探討是否早在後生動物演化時,就已出現微RNA調控ATP合成酶次單體基因的現象,是一個相當有趣的議題。這些微RNA是否對這些次單體基因的表現程度有不同的影響?此影響是否會引起這些次單體表現量的平衡?我們想知道不同的微RNA是否會在相同的時間點被啟動,而當ATP合成酶的表現大量受到微RNA抑制時對細胞造成的結果又是如何?
本計畫主要的目標是要探討在演化上微RNA於ATP合成酶次單元基因調控中所扮演的角色。
特定目標:
1. 預測並實證調控人類ATP合成酶次單體基因的微RNA。
2. 闡明這些微RNA是否對ATP合成酶次單體表現程度有不同的影響,及其所造成的生物性結果為何?是否會抑制癌細胞生長?
3. 研究在動物演化的過程中,調控ATP合成酶次單體基因的微RNA及其調控網路何時被啟動?
4. 找出影響調控ATP合成酶次單體基因的微RNA轉錄因子。在動物演化過程中,這些因子何時被啟動去調控這些微RNA?
在本研究計畫中,我們期望能夠了解調控ATP合成酶次單體基因的微RNA及其網路於動物演化過程中所扮演的角色。此研究也許有助於釐清微RNA於演化的重要性。
Abstract: ATP synthase is a multimeric protein complex that catalyzes the synthesis of ATP. It is essential for almost all organisms because ATP is the common “energy currency” of cells. The modular evolution theory for the origin of ATP synthase suggests that two subunits with independent functions, a DNA helicase with ATPase activity and a H+ motor, were able to bind together, so the rotation of the motor drive the ATPase activity of the helicase in reverse. This would then evolve to become more efficient, and eventually develop into the complex ATP synthases seen today. Since ATP synthase is such an important protein and since it is a complex with many subunits, we are curious as to whether ATP synthase is regulated by many miRNAs. Although protein complex subunit genes tend to be less regulated by miRNAs, our predictions suggest that some ATP synthase subunit genes are targets of different miRNAs. In view of the fact that ATP synthase is an ancient protein, it is interesting to ask whether the miRNA regulation of subunit genes arose early in metazoan evolution. Another question is whether these miRNAs have very different effects on the expression levels of subunit genes, a situation that would pose a problem of dosage balance among the subunits. Indeed, when a subunit gene becomes a new miRNA target, how is the dosage balance among subunits maintained? We therefore ask if the different miRNAs were recruited at similar times. A natural question to ask is what the consequences are when the express level of ATP synthase is substantially reduced by miRNAs. A simple test is to see whether it can suppress cancer growth.
Our major objective is to provide much detail on how the role of miRNAs in ATP synthase subunit gene regulation has been expanded in evolution, especially in the lineage leading to human. Our specific aims are:
1. To predict and validate miRNAs that regulate human ATP synthase subunit genes.
2. To elucidate whether these miRNAs have very different effects on ATP synthase subunit expression levels, what are the biological consequences when the ATP synthase level is significantly reduced by miRNAs and whether it can suppress cancer growth.
3. To study when these miRNAs were recruited to regulate ATP synthase subunit genes during animal evolution and how their regulatory networks have evolved?
4. To find out the transcription factors (TFs) that regulate the key miRNA genes regulating ATP synthase subunit genes. To address the questions: “when were these TFs recruited to regulate the key miRNAs?” “Were they recruited at similar times or at very different times during animal evolution?”
With the proposed study, we expect to understand the roles of the miRNAs that regulate ATP synthase subunit genes in the evolution of regulatory networks during animal evolution. It may provide in-depth information on the impact and importance of the evolution of miRNAs.
Keyword(s)
ATP合成酶
分子演化
微RNA
調控網路
轉錄因子
ATP synthase
molecular evolution
miRNA
regulatory networks
transcription factors