| Abstract: | 相當多的研究報告顯示微型核糖核酸(miRNA)不正常的表達與癌症的生成及轉移 有關。 miRNA 可扮演致癌基因(oncogene, OCG)及抑癌基因(Tumor Suppressor Gene, TSG)的兩種角色。生物體內或試管實驗顯示的甲基化導至 miRNA 基因沉默與癌症形 成有關，故此了解miRNA 表觀遺傳調控在研究癌症是相當重要的課題。此外癌症的生 成與染色體異常(chromosomal abnormality)有相當密切的關係，由染色體異常所引起的 miRNA 基因溶合事件也是這計畫研究的課題之一。 此計畫有如下數方面之工作： (i) 建立人類的全基因組 miRNA 附近的CpG 島訊息，特別是癌症相關之miRNA (ii) 整合全基因組 CpG 島的甲基化形態、過高及過低甲基化之資料， (iii) 探討有關染色體異常，脆弱位置及 miRNA 叢集與癌症之關係， (iv) 整合數種機器學習分類方法作全基因組 miRNA 標靶之預測， (v) 與癌症相關的侯選 miRNA 之表觀遺傳調控探討， (vi) 預測起因於染色體異常的 miRNA 非編碼基因之基因溶合事件 (vii) 建立資料庫，整合染色體異常、脆弱位置及 miRNA 之訊息。 實驗部份將完成如下數方面之工作： (i) 確認預測的 miRNA 及其目標基因在細胞中的表現相關性。 (ii) 以抑制物抑制 miRNA 之表現，觀察相關基因的表現及標靶位置。 (iii) 分析 miRNA 啟動子附近的CpG 島甲基化型態。 (iv) 確認預測的 miRNA 轉錄單位融合事件，及其對下游基因表現之影響。 (v) 研究此 miRNA 對細胞的重要生理現象，如生長與apoptosis 的影響，並研究其分子 機轉 研究結果將建置成網站提供查詢。此網站提供下列的功能，(1) miRNA 附近的CpG 島訊息，特別是與癌症相關的miRNA、(2) 與癌症相關的miRNA 之甲基化形態、過高 及過低甲基化的資料、(3) 與癌症相關的侯選miRNA、(4) 侯選miRNA 之表觀遺傳調 控訊息及(5) 預測之miRNA 非編碼基因的基因溶合與染色體異常訊息。
Many reports have suggested that aberrant microRNA (miRNA) expression is associated with tumor progression and metastasis. MiRNAs could cause cancers by acting as oncogenes (OCG) and tumor suppressor genes (TSG). In vivo or in vitro experiments indicated that the presence of DNA methylation-associated silencing of miRNA is involved in human cancer, hence, it is vital to understand the epigenetic regulatory mechanism of miRNA expression. Furthermore, novel miRNA gene fusion events created by chromosomal abnormality will be investigated. In this proposal we aim to address the following issues, (i) Establish genome-wide CpG island proximal miRNAs, in particular, cancer-related miRNAs; (ii) Integrate genome-wide CpG island methylation pattern, hyper-methylation and hypo-methylation data; (iii) Investigate the roles of chromosomal abnormality, fragile site, and miRNA cluster in miRNA cancer biology; (iv) Genome-wide miRNA target gene prediction by adopting machine learning classifiers; (v) Epigenetic study of putative cancer-related miRNAs (vi) genome-wide novel miRNA non-coding gene fusion events prediction due to abnormality, and (vii) database construction - chromosomal abnormality and fragile site data are overlay with miRNA data For the experimental part, the following tasks will be addressed, (i) elucidate the expression profiles of the predicted miRNAs with those of their target gene in vivo. (ii) will identify the target sites and expression level of cancer-related miRNAs through the use of inhibitor, (iii) elucidated the methylation pattern of promoter proximal CpG island for miRNA genes, (iv) in vivo analysis of predicted miRNA gene fusion events and its effects on downstream genes, and (v) investigate cell physiological effects induced by miRNA, such as the growth and apoptosis mechanisms. Results will be deployed as a web service. This web service will provide the following functionalities, (1) CpG island proximal miRNAs, in particular, cancer-related miRNAs; (2) methylation pattern, hyper-methylation and hypo-methylation data for cancer-related miRNA genes, (3) putative cancer-related miRNAs, (4) epigenetic information for putative cancer-related miRNAs, and (5) miRNA gene fusion events due to chromosomal abnormality |
