神經生長因子在神經分化中轉錄因子活性及基因調控機制之橫觀

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姓名

洪一靈(Yi-Lin Hung) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

神經生長因子在神經分化中轉錄因子活性及基因調控機制之橫觀
(Integrating Transcription Factor Activities and Gene Regulation in NGF-Induced Neuron Differentiation)

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摘要(中)

轉錄作用(transcription)在細胞生長及分化等生物過程中基因調控扮演非常重要的角色，轉錄機制受到基因本身與轉錄因子 (Transcription factors) 這些蛋白質相互作用的行為以及被調控基因產生之蛋白質對其他基因的回饋性調控，要了解複雜的基因調控-表達-回饋的過程，必須以系統生物學觀念，運用高通量檢測及資訊分析等方法來了解基因調控之網絡。
我們研究神經生長因子 (NGF) 在早期PC-12細胞分化成類神經細胞中，轉錄過程中的調控機制，對已知345個轉錄因子進行轉錄因子-核酸矩陣列實驗及利用大鼠外顯子1.0晶片分析整體基因表現；由高通量轉錄因子變化，系統性觀察基因受到調控機制。在轉錄因子陣列實驗中，PC-12細胞加入神經因子之後，有71%的轉錄因子受到明顯調控；在與c-AMP 路徑調控有關之轉錄因子當中，有七成的轉錄因子有明顯變化。在大鼠外顯子1.0晶片實驗結果中，利用Partek找出有明顯變化的1546個基因，並做基因功能的分類。並找出轉錄因子AP-1、AP-2、CREB及EGR2等上下游基因，作初步的比對，找到與神經分化有關基因Il-11及Unc5c，而其他基因，推測與早期PC-12細胞分化有關。本研究利用神經因子刺激PC12 細胞為主軸以高通量微陣列晶片的技術利用系統生物學來整合基因調控元素及轉錄因子之間複雜的關係與交互作用，並希望未來能將這些轉錄因子上下游基因找出建資料庫，並與整體基因表現做連結探討。

摘要(英)

Transcription plays a very important role on gene regulation of cell growth and differentiation. The interaction between gene and protein and the transcription of their own genes, as well as the formation of negative feedback loops are the factors to　affect gene regulation. In order to understand this complex systemic network, we　apply high-throughput way and statistical methodologies. In our study, we compared the result of protein/DNA array which contain 345 transcription factors (TFs) and exon array which can analysis expression of whole gene to explore the signal transduction and regulation of upstream and downstream genes in the NGF-signal pathway in PC12 nuclei. We find, first, 71% TFs would be regulated significantly after NGF treat. Expression of 70% TFs change significantly in c-AMP pathway. Second, in exon array, using Partek software to find 1546 genes which p-value < 0.5 and then classify these genes by GO. Third, we find the up/down stream genes of TFs- AP-1、AP-2、CREB and EGR2. Among these genes, Il-11 and Unc5c are associated with neuronal differentiation; others are inferred to early cell differentiation on PC12. Future, we want to find up/down stream genes of these TFs and establish the database to connect with whole gene expression.

關鍵字(中)

★ 神經生長因子
★ 外顯子晶片
★ 轉錄因子
★ 神經分化

關鍵字(英)

★ Transcription factor
★ Exon array
★ NGF
★ Neuron differentiation

論文目次

摘要 i
ABSTRACT ii
致　謝 iii
目錄 iv
圖目錄 vi
表目錄 vii
縮寫表 viii
第一章緒論 1
1-1 神經細胞特性與發育 1
1-2 神經生長因子 2
1-3 神經生長因子作用機制 3
1-4 神經生長因子調控嗜鉻性細胞瘤細胞分化 7
1-5 研究緣起 8
第二章實驗材料與方法 9
2-1 實驗材料 9
2-2 實驗方法 11
第三章結果 26
3-1 嗜鉻性細胞瘤細胞分化為類神經細胞 26
3-2 轉錄因子核酸矩陣列分析方法結果 26
3-3外顯子全轉錄本1.0晶片分析方法結果 29
3-4 轉錄因子上下游基因初步尋找結果 30
第四章討論 32
4-1 大鼠嗜鉻性瘤細胞的分化 32
4-2 轉錄因子陣列分析 32
4-3 基因功能分類討論 33
4-4 轉錄因子上下游基因討論 34
第五章結論 35

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指導教授

凌慶東(Qing-Dong Ling)

審核日期

2009-7-23

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