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研究生:姜佳良
研究生(外文):Jia-Liang Jiang
論文名稱:小鼠肝再生中印痕基因的表現以及基因甲基化之探討
論文名稱(外文):Expression profile and methylation pattern of imprinted genes in liver regeneration
指導教授:鄒安平
指導教授(外文):Ann-Ping Tsou
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:84
中文關鍵詞:印痕基因微陣列肝再生甲基化
外文關鍵詞:imprinted genesmicroarrayliver regenerationmethylation
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肝癌是非常普遍的惡性腫瘤,通常肝癌發生的原因是因為病毒長期感染或其他化學致癌因子不斷傷害肝臟所造成的。當肝臟受到外來傷害時,肝細胞會再生以維持肝臟的功能和質量。正常的肝再生過程牽涉許多基因,以及不同的基因及後基因調控機制,確保肝細胞的細胞週期受到嚴密的調控。當肝細胞的細胞週期失控時,便會導致肝細胞走向癌化。我們以小鼠部分切肝模式為背景,以微陣列為工具,大規模分析肝再生過程中基因表現的變化,藉此研究肝再生的詳細機制。印痕是特殊的後基因調節機制,藉由甲基化及其他修飾,細胞能分辨來自不同親源的對偶基因並表現其中之一。大部分的印痕基因在對偶基因上有不同甲基化區域可做為細胞分辨親源的標記。印痕基因在細胞生長、胚胎發育及行為發展上扮演重要的角色。本實驗室先前發表印痕基因Peg10在切肝後48 小時到96 小時表現量增加,但其他印痕基因在肝再生過程中的表現並無詳細的描述。我們藉由比對公開的印痕基因資料庫和肝再生微陣列找出在肝再生過程中有表現的印痕基因,發現在肝再生過程中表現的印痕基因其功能和調控細胞生長有關,包括細胞的增生、細胞周期的調控及細胞的凋亡。我們從這些基因中挑選四個表現量變化超過1.5 倍的印痕基因Dlk1、Grb10、Mest及H19,以亞硫酸氫鈉修飾方式研究這些基因不同甲基化區域的甲基化變化在肝再生過程中的變化情形,以及此變化和表現量間的關聯性。結果發現Dlk1、Grb10、Mest在不同時間點的甲基化並沒有改變, H19的甲基化變化雖有改變,但和基因表現量變化似乎沒有直接的關聯性。本實驗證明在肝再生過程中控制印痕基因表現量的主要因素並非完全依賴甲基化的程度,可能是其他的基因調控機制,如轉錄因子的活性,控制印痕基因的表現。本論文是首次利用微陣列方式探討印痕基因在肝再生中的表現以及甲基化所扮演的角色之報告。
Imprinting is an important epigenetic regulation. Cells can
distinguish parental origin of different alleles and express the correct one.
As a recognition marker, most of the imprinted genes have differentially methlyated region (DMR) on the two alleles. Imprinted genes play important roles in embryonal development and behavior. We previously reported Peg10, an imprinted gene that was expressed at 48 hours to 96 hours after partial hepatectomy (PHx) but a systematic investigation of imprinted genes in liver regeneration has been lacking.We combined the information from several public databases of imprinted genes with a microarray dataset of liver regeneration to identify expression of many candidate imprinted genes. These genes have
potential to participate in regulation of cell growth and apoptosis based on their known biological functions. In an attempt to correlate the methylation patterns at DMR with gene expression, four genes, Dlk1,Grb10, Mest and H19 were studied in this work. We found no detectable variation of methylation pattern at DMR of Dlk1, Grb10 and Mest while
significant reduction of DMR methylation was found in H19 at PHx 36h and 96h. Since the expression level of H19 did not correlate linearly with the altered pattern of methylation, we speculate that other mechanisms such as regulation by cirtical transcription factors may play important role in controlling gene expression of H19. This is the first time that such a global strategy was applied to explore the methylation status of potentially imprinted genes during liver regeneration.
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