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研究生(外文):Hung-cheng Li
論文名稱(外文):Functional study of transcription repressor Z40A/ZNF266 on the promoter of squamous cell carcinoma antigen recognized by T cells 3 (SART3)
指導教授(外文):Wen-chang LinJiann-Shiun Lai
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Krüpple型鋅指 (zinc finger) 基因廣泛存在於不同生物體系中,推測人類基因組中有700個以上Krüpple型鋅指基因是目前所發現最大的蛋白質家族而大部分Krüpple家族基因的生物功能仍不是很清楚。已知功能的Krüpple型鋅指基因多與生長及發育有關。
Z40A/ZNF266為一個新型Krüpple型鋅指蛋白質。Z40A/ZNF266的開放讀碼區 (open reading frame) 是由6個外顯子 (exon) 所組成,含有616個胺基酸,主要包含Krüpple-associated box (KRAB) 區域和12個連續的C2H2型鋅指結構,分別位在N端及C端。Z40A/ZNF266廣泛表現在淋巴器官和非淋巴組織。Z40A/ZNF266表現在淋巴器官有脾臟、胸腺、周邊血液白血球和淋巴結;而Z40A/ZNF266表現在非淋巴組織則有睪丸、直腸、胃臟和甲狀腺。從生化功能上分析已知Z40A/ZNF266藉由KRAB區域進行轉錄抑制的功能;同時利用任意DNA結合位置篩選的方法確定Z40A/ZNF266 DNA結合位置的共通序列為5’GGCGATAAGTAA3’。
為更進一步地了解Z40A/ZNF266的生物功能,我們利用中研院生醫所常蘭陽博士實驗室設計的電腦程式搜尋Z40A/ZNF266的DNA結合序列存在於哪些標靶基因的啟動子,試圖了解Z40A/ZNF266調控生物功能的可能機制。本篇論文主要的工作是藉由Z40A/ZNF266 DNA結合位置的共通序列搜尋所得到其中一個Z40A/ZNF266的標靶基因,squamous cell carcinoma antigen recognized by T cells 3 (SART3),針對其做啟動子分析實驗 (promoter assay) 探討SART3啟動子的Z40A/ZNF266 DNA結合序列是否會受到外生性 (exogenous) 表現的Z40A/ZNF266所調控。並利用染色體免疫沈澱實驗 [chromatin immunoprecipitation (ChIP) assay] 分析Z40A/ZNF266結合在標靶基因的啟動子的可能性。並且利用RNA干擾實驗以siRNA knockdown內源性 (endogenous) Z40A/ZNF266基因的表現,觀察SART3標靶基因是否受到Z40A/ZNF266的調控。由啟動子分析實驗,外生性表現的Z40A/ZNF266在SART3啟動子有14%些微的轉錄抑制活性,但是為了避免受到內源性Z40A/ZNF266在此DNA結合序列的競爭,將外生性表現的Z40A/ZNF266融合VP16的轉錄活化區域 (activation domain),使得Z40A/ZNF266從轉錄抑制子變成轉錄活化子,此實驗結果發現報導基因 (reporter gene) 的轉錄活性有2倍的增加;同時在SART3啟動子不含Z40A/ZNF266 DNA結合序列時,發現所有的報導基因的轉錄活性都上升將近2倍,此結果發現Z40A/ZNF266能透過結合在SART3啟動子的Z40A/ZNF266 DNA結合位置抑制標靶基因SART3的表現。同時透過ChIP assay在體內 (in vivo) 情況下,發現Z40A/ZNF266和其輔助抑制子KRAB-associated protein-1形成複合體結合在標靶基因SART3啟動子上;除此之外,histone deacetylase-1、heterochromatin protein 1也發現會結合在SART3啟動子上,顯示SART3基因可能位在異染色質 (heterochromatin) 區域。最後以siRNA knockdown內源性Z40A/ZNF266的RNA表現,結果在siRNA knockdown內源性Z40A/ZNF266 48小時後當Z40A/ZNF266 RNA表現剩下9%的表現時,SART3的RNA表現卻只有些微上升17%,可能因為SART3啟動子只有一個Z40A/ZNF266 DNA結合位置,單獨排除內源性Z40A/ZNF266對於SART3基因的表現並沒有足夠的影響也有可能knockdown內源性Z40A/ZNF266後,其他含有KRAB區域的Krüpple型鋅指蛋白質可以結合在和Z40A/ZNF266相同的DNA結合位置持續調控SART3基因的表現,詳細可見討論。經由上述三項實驗結果發現Z40A/ZNF266可以透過SART3啟動子的Z40A/ZNF266 DNA結合位置調控SART3基因的表現。
Krüpple type zinc finger genes are widely present in different biology but their biological function is still unclear. At present, there are more than 700 Krüpple type zinc finger genes that involve in cell growth and differentiation in the human genome.
Z40A/ZNF266 is a novel Krüpple type zinc finger protein and its open reading frame contains six exons encoding 616 amino acids. Z40A/ZNF266 protein consists of two conserved domains: a Krüpple-associated box (KRAB) at the amino terminus and 12 consecutive C2H2 type zinc finger motifs at the carboxyl terminus. The Z40A/ZNF266 transcripts are broadly expressed among tissues, although it is not expressed ubiquitously. The transcripts not only predominantly expressed in lymphoid organs like spleen, thymus, peripheral blood leukocyte, and lymph node, but it also highly expresses in other nonlymphoid tissues, such as testis, colon, stomach, and thyroid. Through biochemical assays, the KRAB domain of Z40A/ZNF266 bears transcriptional repression activity. Using random DNA binding site selection method, we have identified that the DNA binding consensus sequence of Z40A/ZNF266 is 5’GGCGATAAGTAA3’.
To understand the biological function of Z40A/ZNF266, we have searched the putative target genes of Z40A/ZNF266 using computer program made by Dr. Ch’ang, L.-Y. lab. One of the candidates, squamous cell carcinoma antigen recognized by T cell 3 (SART3) contains the DNA binding consensus sequence of Z40A/ZNF266 at the promoter region upstream of 380 bps from its transcriptional starting site. By employing the promoter assay, chromatin immunoprecipitation (ChIP) assay, and siRNA knockdown experiment, we have found that: First, the transcriptional repression activity of luciferase reporter gene, which was driven by SART3 promoter, decreases about 14% when transient expression of Z40A/ZNF266 in the cells by promoter assay. To avoid endogenous Z40A/ZNF266 competing with exogenous Z40A/ZNF266 in the promoter assay, we then converted Z40A/ZNF266 to transcriptional activator fusion Z40A/ZNF266 with herpes viral protein VP16 activation domain. As a result, the reporter activity arises two folds, suggesting exogenous Z40A/ZNF266 binds to SART3 promoter in the cells. This result is further supported by the fact that the basal transcriptional activity of reporter gene without Z40A/ZNF266 binding site on the SART3 promoter is also about two folds higher than the activity of reporter gene with the Z40A/ZNF266 binding site on the SART3 promoter in the cells. Second, by using ChIP assay, the results show that Z40A/ZNF266 can be specifically crosslinked to the Z40A/ZNF266 DNA binding site on the endogenous SART3 promoter, so does KRAB-associated protein-1, the transcriptional corepressor of Z40A/ZNF266. Furthermore, the proteins involving in heterochromatin formation, such as histone deacetylase-1 and heterochromatin protein 1, are both bound to the promoter region of SART3 promoter, suggesting SART3 gene promoter associates with heterochromatin structure. Third, after 48 hours transiently transfection of small RNA duplexes of Z40A/ZNF266 to the cells, the expression of Z40A/ZNF266 transcript is significantly down to about 9% left; however, the expression of endogenous SART3 transcript only slightly increases 17% or so. It could be Z40A/ZNF266 is only one of the components on the complicate regulatory promoter of the SART3 gene. It might also be due to the redundancy activity of the zinc finger proteins on the SART3 promoter. There are several hypothses addressed in details in the chapter of Discuss. In conclusion, we have employed three different approaches to demonstrate that Z40A/ZNF266 binds to its binding site on the promoter of SART3 gene and it suggests that SART3 is the target gene of Z40A/ZNF266.
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