蛋白質精胺酸甲基化由蛋白質精胺酸甲基轉移脢所催化，和訊息傳遞、 轉錄調控、 RNA處理和DNA修補等相關。本研究將焦點放在唯一神經細胞特異性表達的PRMT8上。PRMT8是度保留最高的PRMT1脊椎動物中的平行同源基因。二者主要差異在不同物種中PRMT8均含多出60-90個胺基酸長度的N端。本研究希望回答PRMT8為何及如何不同於PRMT1，以及PRMT8的生理功能為何，並將聚焦於其可能參與的神經疾病及癌症。為探討PRMT8的相關課題，我們將對其基因結構、剪接模式及可能的轉錄調節單元進行生物資訊分析，以追蹤PRMT8在演化中改變。我們將分析PRMT8和部分 PRMT1 異構體的甲基轉移脢活性以及其於神經細胞中的交互作用體，以描繪PRMT8特有的交互作用網。我們將訂出不同PRMT8/(PRMT1)異構體在一般及壓力條件下的表現形式，以檢查他們可否能參與神經退化性疾病。我們也將研究PRMT8可否在癌症中表現並扮演某些角色。我們還將分析PRMT8的轉錄調節。最後我們會以斑馬魚為系統來驗證或補充在哺乳動物細胞中所得結果。由本研究所提實驗獲致的結果，我們將能勾勒出較細節的PRMT8特有精胺酸甲基化網絡以及PRMT8在生理和病理上的角色。
Protein arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is involved in various cellular processes including signal transduction, transcriptional regulation, RNA processing, and DNA repair. In this study we will focus on PRMT8, the only neuron-specific PRMT. PRMT8 is a vertebrate-specific paralogue of the most conserved PRMT1. The major difference between the two is that PRMT8 contains an extra N-terminus for about 60-90 amino acids in different species. In this study we would like to answer why and how PRMT8 is different from PRMT1 and what is the physiological function of PRMT8, with the focus on its putative participation in the pathogenesis of neural disorders or cancers. We will pursue the issues of PRMT8 by conducting bioinformatic analyses of the gene structure, splicing pattern, the putative transcriptional regulatory elements of the prmt8 gene, and tracing the changes of the segments in the N-terminus of PRMT8 through evolutionary. We then will analyze the methyltransferase activity of PRMT8 and specific PRMT1 isoforms, and also the interactome of human PRMT8 in the neuronal cells to picture the PRMT8-specific interaction network. We will determine the expression pattern of different PRMT8/(PRMT1) isoforms under normal and stress conditions to examine their putative involvement in neural degenerative disease. We will also study the putative expression and roles of PRMT8 in cancer. We will also analyze transcriptional regulation of prmt8. Finally, we will use zebrafish as the biological system to validate and complement the results from studies of the mammalian cell cultures. With the results of the experiments proposed in this project, we can outline a more detailed PRMT8-specifc arginine methylation network and the physiological and pathological roles of PRMT8.
