臺灣博碩士論文加值系統

非編碼RNA在蛋白質轉譯、基因剪接、RNA修飾、RNA加工和調控基因表現扮演重要的角色。隨著分子生物學新技術的發展和新種類非編碼RNA的發現，尋找更多非編碼RNA的方法也不斷革新。高效能定序技術對20-30 nt small regulatory RNA的研究有很大的貢獻。高效能大量定序18-26 nt small RNA所產生的資料中不只包含了small regulatory RNA，也包括了從編碼或非編碼RNA降解而來的小片段產物。在分析大量small RNA序列資料時，選擇適當的計算方法對區分不同來源的small RNA、是否可以發掘新類型的非編碼RNA以及可否揭露其中所隱含的知識有決定性的影響。目前大部分計算方法的發展都集中在尋找microRNA (miRNA)。應用small RNA定序資料在研究其它非編碼RNA的計算方法，尚付之闕如。本論文著重於發展新的生物資訊方法來分析small RNA定序資料，以增進對阿拉伯芥非編碼RNA的了解。
本研究第一部分利用資料庫中大量阿拉伯芥small RNA 序列資料，開發新的生物資訊方法來尋找一種稱為trans-acting siRNA (ta-siRNA)的small regulatory RNA。不同於其它siRNA, 此類siRNA的生合成需要miRNA促成的截切。此外，大部分的ta-siRNA彼此之間和相對於截切點的距離是21的倍數。利用此一特點，本論文開發出第一個計算方法可以從複雜的small RNA序列資料中成功地找到已知和新的會產生ta-siRNA的阿拉伯芥基因。不同於以往發現的ta-siRNAs，其中一群新發現的ta-siRNAs的生合成需要的是另一個ta-siRNA促成的截切，而不是miRNA。本研究結果發現了一條前所未見的small regulatory RNA之連鎖生合成路徑。這路徑從一個miRNA開始，緊接著的是連續兩階層ta-siRNA的產生。
第二部分，則是應用small RNA序列資料去尋找小核仁RNA（small nucleolar RNA）。過去的研究多認為從小核仁RNA來的small RNA是降解而來的產物，所以多予以忽略而未詳加分析。但從分析阿拉伯芥small RNA序列資料中，我發現小核仁RNA的兩端會產生較多的small RNA。利用這樣的特性，本論文得以發展出新的運算方法，來重新註解缺乏明確邊界的小核仁RNA和發掘新的小核仁RNA。而根據這些新找到的小核仁RNA,也得以進一步推論出阿拉伯芥核糖體RNA(rRNA)和剪接體小核內RNA(small nuclear RNA)上存在有先前未鑑定出的RNA修飾點。
本研究顯示，結合生物學已知知識和大量核酸定序資料，可以推衍出嶄新的生物資訊演算法，用於探勘分析small RNA序列資料，對small regulatory RNA或其它非編碼RNA的研究有莫大的助益。

Non-coding RNAs (ncRNAs) play vital roles in translation, splicing, RNA processing, RNA modification and regulation of gene expression. The advancement in ncRNA discovery is evolving along with the finding of new classes of ncRNAs and the invention of revolutionary sequencing platforms. High-throughput sequencing technologies greatly facilitate the study of small regulatory RNAs which are 20 to 30 nt in length. High-throughput sequencing data of 18-26 nt small RNA fragments are a mixture of small regulatory RNAs and degraded products from coding RNAs or ncRNAs. The proper choice of computational approaches in analyzing small RNA sequencing data is crucial for the dissection of small RNAs derived from distinct origins, for making discovery of new ncRNAs and for revealing embedded knowledge in these ncRNAs. To date, the development of computational approaches mostly focused on the discovery of microRNAs (miRNAs). Computational approaches which use small RNA sequencing data for the studies of other ncRNAs are much in need. This dissertation presents the development of novel bioinformatics approaches to analyze small RNA sequencing data and showed that the analyses have increased the understandings of Arabidopsis ncRNAs.
In first part, by the use of abundant small RNA sequencing data from the public domain, a new bioinformatics approach was developed for the finding of trans-acting small interfering RNAs (ta-siRNAs), a new class of small regulatory RNAs. Different from that of other siRNAs, the biogenesis of ta-siRNAs is dependent on the cleavage directed by miRNAs. Moreover, most ta-siRNAs are clustered in 21-nt increments relative to the cleavage site. Based on this characteristic, this study developed the first computational algorithm which successfully recovered both known and novel Arabidopsis loci producing ta-siRNAs from complex small RNA sequencing data. A group of newly identified ta-siRNAs was produced by the cleavage directed by a ta-siRNA instead of by miRNAs as was reported previously. The results indicate the existence of a small RNA regulatory cascade initiated by miRNA-directed cleavage and followed by the consecutive production of ta-siRNAs.
The second part focuses on the use of small RNA sequencing data in the annotation of small nucleolar RNAs (snoRNAs). Small RNAs from snoRNAs are often considered to be degraded products of snoRNAs and were filtered out without further analysis in previous studies. However, the analysis of Arabidopsis small RNA sequencing data revealed an enrichment of small RNAs at the termini of snoRNAs. With the use of this feature, this study developed a new method which was able to re-annotate known snoRNAs lacking well defined termini and to discover novel snoRNA species. The finding of new snoRNAs also supported that there are additional RNA modification sites on Arabidopsis ribosomal RNAs and spliceosomal small nuclear RNAs.
This research demonstrates that, by combining pre-existing biological knowledge and appropriate mining approaches, small RNA sequencing data represent a wealth treasure for the studies of small regulatory RNAs as well as other ncRNAs.

中文摘要 i
Abstract iii
Lists of Tables vi
Lists of Figures vii
Lists of Appendixes viii
Part 1. Introduciton of Non-coding RNAs 1
Part 2. Identification of Arabidopsis Gene Producing Trans-acting siRNAs 7
Abstract 8
Introduction 9
Materials and Methods 13
Results 16
Discussion 24
Part 3. Expanding Arabidopsis Small Nucleolar RNAs by Mining Small RNA Sequencing Data 38
Abstract 39
Introduction 40
Materials and Methods 43
Results 49
Discussion 57
Part 4. Future Prospects 73
References 78
Appendixes 86

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