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研究生:張文政
研究生(外文):Wen-Cheng Chang
論文名稱:人類U12型內含子及參與mRNA代謝之RNA結合蛋白之生物資訊及功能分析
論文名稱(外文):Bioinformatic and functional analysis of human U12-type introns and RNA-bindig proteins involved in mRNA metabolism
指導教授:譚婉玉
指導教授(外文):Woan-Yuh Tarn
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:英文
論文頁數:101
外文關鍵詞:alternative splicingU12-type intronJNK2/MAPK9hybrid intronWDFY1RBM4DDX3
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RNA 序列或是 RNA 結合物會調控 RNA 的代謝過程。本論文除了探討人類 U12 型內含子 (intron) 的選擇性剪接,也企圖找尋可受 RBM4 和 DDX3 調控的 mRNAs。U12 型內含子高度保留於各類後生動物 (metazoan)。U12 型內含子的剪接發生於和 U2 型剪接體極為不同的 U12 型剪接體中。由於兩種剪接體不具有相容性,任何與 U12 型內含子有關的選擇性剪接將相對地使基因表現變得更為複雜。我們研究了 U12 型內含子的選擇性剪接,以期對其機制有更深入的瞭解。首先,我們以人類 JNK2 基因中罕見的具有 U12 型 5’剪接位 (splice site) 和 U2 型 3’剪接位之混雜型內含子 (hybrid intron) 的外顯子互斥型選擇 (mutually exclusive exon selection) 為描述對象。我們證明了在混雜型內含子中一段很長並具高度演化保留性的 polypyrimidine tract 提供了選擇下游外顯子的重要訊號。此外,我們還驗證了在人類 WDFY1 基因的 U12 型內含子中,單一核苷酸多型性對於 pre-mRNA 剪接的影響。實驗結果提供了對於 U12 型內含子剪接位選擇機制的推斷。我們也討論了當 U12 型內含子有基因缺陷時對剪接的潛在影響,以及一部分含有 U12 型內含子的 RNA processing factors 可能會影響整體基因表現的效果。最後,利用生物資訊的分析,我們找到了部分在肌肉細胞分化過程中進行選擇性剪接時可能會受到 RBM4 所調節的 pre-mRNAs,以及在轉譯作用啟始時或許會受 DDX3 所調控的 mRNAs。
RNA metabolism is regulated by interplay between cis-elements and trans-factors. We studied alternative splicing of human U12-type introns, and also searched for the potential mRNA targets of RBM4 and DDX3 proteins. U12-type introns exist and are conserved in a variety of metazoan. Splicing of U12 intron-containing precursor mRNAs takes place in the U12-type spliceosome that is distinct from the U2-type spliceosome. Due to functional incompatibility of these two spliceosomes, alternative splicing involving a U12-type intron may result in a relatively complicated impact on gene expression. We studied alternative U12-type intron splicing in an attempt to gain more mechanistic insights. First, we characterized mutually exclusive exon selection of the human JNK2 gene, which involves an unusual hybrid intron possessing the U12-type 5’ splice site and the U2-type 3’ splice site. We demonstrated that the long and evolutionary conserved polypyrimidine tract of this hybrid intron provides important signals for inclusion of its downstream alternative exon. In addition, we examined the effects of single nucleotide polymorphisms in the human WDFY1 U12-type intron on pre-mRNA splicing. These results provide mechanistic implications on splice site selection of U12-type intron splicing. We also discussed the potential effects of splicing of a U12-type intron with genetic defects or within a set of genes encoding RNA processing factors on global gene expression. Finally, using bioinformatic analysis, we analyzed potential pre-mRNA targets of RBM4 that undergo alternative splicing during muscle cell differentiation, and mRNA targets that are translationally regulated by DDX3.
Table of Contents
Page
Contents I
List of figures IV
List of tables V
中文摘要 01
Abstract 02
Chapter I. General Introduction 03
1.1 General features of gene transcripts 04
1.1.1 The spliceosomal introns 04
1.1.2 U12-type introns in evolution 05
1.2 RNA binding proteins and their mRNA targets 06
1.2.1 RBM4 07
1.2.2 DDX3 08
1.3 Specific Aims 10
Chapter II. Methods and Materials 12
2.1 Computational analysis of U12-type introns 13
2.1.1 Sequence conservation surrounding the hybrid intron 13
2.1.2 SNP surrounding the U12-type intron 14
2.1.3 Computational analysis of RBM4 target candidates 14
2.1.4 Computational analysis of DDX3 target candidates 15
2.2 Plasmid construction 16
2.2.1 Construction JNK2 minigenes 16
2.2.2 Construction WDFY1 minigenes 17
2.2.3 Construction Nova protein expression vector 18
2.3 In vivo splicing assay 19
2.4 DNA recovered from chromatography paper 20
2.5 In vitro preparation of Nova proteins 20
2.6 In vitro transcribed the 32P-labeled RNA substrate 20
2.7 Gel mobility shift assay 21
Chapter III. Results 22
Part I: U12-type intron and alternative splicing 23
3.1 Searching for more human U12-type introns 23
3.2 U2-U12 hybrid intron and the alternative splicing of hJNK2 24
3.2.1 Hybrid intron architectures 24
3.2.2 Alternative splicing of JNK2 in different cell lines 24
3.2.3 Role of hybrid intron in JNK2 alternative splicing 25
3.2.4 Association of Nova protein with hybrid intron 26
3.3 Effects of SNPs in Alternative Splicing of a U12-type Intron 27
3.3.1 Cryptic 5’ SS utilization is induced by a mutation in the 5’ SS consensus
sequence of the U12-type intron. 28
3.3.2 A branch site mutation of the U12-type intron causes aberrant selection of
both 5’ and 3’ SSs. 28
3.3.3 A 5’ SS and branch site double mutation suppresses U12-type spliceosome-
mediated splicing. 29
3.3.4 Aberrant splicing caused by a branch site mutation can be corrected by a
compensatory U12 snRNA mutant. 29
3.4 U12-type introns in mRNA processing factors 30
3.5 Multiple U12-type intron-containing genes 31
3.6 A U2-type intron within a U12-type intron 32
Part II: RNA-binding proteins and their regulated transcripts 34
3.7 RBM4 and its potential alternative splicing targets 34
3.8 Regulation of mRNA translation by DDX3 35
Chapter IV. Discussions and future perspectives 37
4.1 U12-type intron and alternative splicing 38
4.2 Other effects of the rare U11 snRNP 41
4.3 An intron within an intron 42
4.4 RBM4 and its potential alternative splicing targets 43
4.5 RBM4 binding elements- and U12-type intron-mediated alternative splicing 44
4.6 Other roles of RBM4 in mRNA processing 44
4.7 DDX3 and its regulating transcripts in translation 45
Bibliography 46
Figures 56
Tables 73
Appendices

List of Figures
Figure 01. The U2-U12 hybrid intron in the MAPK family members. 56
Figure 02. Human JNK2 partial genome and minigenes. 57
Figure 03. The role of the U2–U12 hybrid intron in alternative splicing of human JNK2
pre-mRNA. 58
Figure 04. Sequence conservation surrounding the JNK2 hybrid intron. 59
Figure 05. Model of mutually exclusive selection of JNK2 exon 6a and 6b. 60
Figure 06. Association of Nova proteins with the Py tract. 61
Figure 07. Human WDFY1 partial genome and minigenes. A. 62
Figure 08. Effect of U12-type intron SNPs in alternative splicing of WDFY1 minigenes. 63
Figure 09. Aberrant splicing caused by a branch-site mutation can be corrected by a 64
compensatory U12 snRNA mutant.
Figure 10. Model shows alternative splicing of the WDFY1 U12-type intron induced by
genetic mutations. 65
Figure 11. U12-type introns present in splicing factor genes may impact on gene expression. 66
Figure 12. Alternative splicing of the human DERL2/DERL3 pre-mRNA. 67
Figure 13. The ‘twintron’ of the Drosophila prospero pre-mRNA. 68
Figure 14. The intro in intron architecture of human SFRS13A pre-mRNA. 69
Figure 15. 5’ UTR features comparison between DDX3 regulated and the general transcripts. 70
Figure 16. Phylogenetic tree analysis of upstream exons of U12-type intron in MAPK
family members. 71
Figure 17. Alternative 5’ or 3’ splice site selection of U12-type intron-containing pre-mRNAs. 72

List of Tables
Table 01. Newly identified human U12-type introns 73
Table 02. SNP near or adjacent to the U12-type intron 76
Table 03. U12-type intron in functional related genes. 77
Table 04. U12-type intron-containing genes involved in RNA metabolism 78
Table 05. U12-type intron in gene families. 79
Table 06. U12-type intron genes with WD40-repeat domain 81
Table 07. Multiple U12-type introns-containing genes 82
Table 08. JNKs in different species and the hybrid introns. 83
Table 09. Gene numbers in different processes of filtering the RBM4 candidates 84
Table 10. Genes with muscle specific alternative splicing patterns 85
Table 11. RBM4 binding motifs in intron the upstream of cassette exon 88
Table 12. RBM4 binding motifs in intron the downstream of cassette exon 89
Table 13. List of disease-associated human genes that undergo muscle specific alternative
splicing 90
Table 14. 5’ UTR features of DDX3-regulated mRNA candidates 91
Table 15. 5’ UTR features of Random01 94
Table 16. 5’ UTR features of Random02 97
Table 17. Bioinformatic analysis of potential DDX3 target mRNAs 100
Table 18. Potential DDX3 target mRNAs that encode cell cycle regulators 101
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