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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54767完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳君泰 | |
| dc.contributor.author | Wei-Yu Chen | en |
| dc.contributor.author | 陳薇聿 | zh_TW |
| dc.date.accessioned | 2021-06-16T03:38:07Z | - |
| dc.date.available | 2020-04-01 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-03-31 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54767 | - |
| dc.description.abstract | CRL4 E3 泛素連接酶參與許多不同的細胞行為，例如細胞週期、DNA修復反應、 染色體重建和細胞訊號傳導。但對其在神經系統的角色的了解仍很少。我們利用果蠅遺傳學篩選發現了CRL4泛素連接酶的受質接受者，dBRWD3，是人類造成智能障礙的致病基因BRWD3 的同源基因，與CRL4一同正向調控Wg signaling。基因剔除dBRWD3在基因學上會使顯性負向作用的Cullin4所造成Wg 缺失的翅膀邊緣缺角的表型更嚴重。Wg signaling 下游目標蛋白，Senseless 和 Distalless的表現需要dBRWD3。我們證明了與抑制轉錄有關的組蛋白修飾，像是H3K9 或H3K27甲基化的表現是需要dBRWD3。更進一步地，與促進轉錄有關的組蛋白修飾，像是H3K9、H3K27或 H3K56乙醯化的表現量，在dBRWD3 突變時會累積，表示dBRWD3 對轉錄可能是負向調控的角色。 透過遺傳學篩選找出和dBRWD3有關的調控者，我們找到組蛋白H3的變異型，組蛋白H3.3，和其分子伴侶HIRA/Yemanuclein (YEM) 複合體，都可以抑制dBRWD3 缺失所導致的rough eye 表型。在dBRWD3 突變時，累積的組蛋白H3.3 破壞基因表現、樹突形態和感覺器官的分化。將yem 或組蛋白 H3.3去活性後能顯著地抑制dBRWD3 突變所造成整體轉錄組的改變和許多發育上的缺陷。HIRA/ YEM複合體所負責的非依賴DNA複製能使組蛋白H3.3加入染色質的過程是一個 核小體替換的機制，對已不複製的神經細胞而言尤其重要。我們的發現指出dBRWD3負責調控轉錄背後的分子機制是透過抑制將組蛋白H3.3加入染色質的 HIRA/ YEM複合體。我們的資料暗示失控的組蛋白H3.3加入染色質會影響基因轉錄，意指dBRWD3 促進Wg signaling可能是透過負向調控組蛋白H3.3加入Wg signaling下游的目標基因上。 我們的工作建立了一個前所未知的對組蛋白H3.3負向調控的機制，此機制對基因表現是重要的，同時也進一步拓展了我們的對dBRWD3缺失所造成的智能障礙的認識。 | zh_TW |
| dc.description.abstract | Cullin RING E3 ligase 4 (CRL4) involves in different cellular processes such as cell cycle, DNA damage response, chromatin remodeling and signaling. Yet little is known about its neurological role. We use a Drosophila genetic screen to identify a substrate receptor of CRL4, dBRWD3, the Drosophila ortholog of the intellectual disability gene Bromodomain and WD40-repeat containing protein 3 (BRWD3), as a positive regulator for Wingless (Wg) signaling. Knockdown of dBRWD3 enhanced Wg-related wing margin notches caused by dominant negative Cullin4. dBRWD3 is required for expression of Wg downstream target, Senseless and Distalless. We identify dBRWD3 is essential for the levels of histone marks associated with transcriptional repressions such as H3K9 methylation or H3K27 methylaiton. Furthermore, the level of histone marks associated with transcriptional activation such as acetylation on H3K9, H3K27 or H3K56 are accumulated in dBRWD3 mutants, indicating dBRWD3 may be a negative regulator of transcription. Through a genetic screen searching for dBRWD3 modifier, we find histone H3 variant, histone H3.3, and its chaperone, HIRA/Yemanuclein (YEM) complex are suppressors in dBRWD3 depletion-induced rough eye phenotype. In dBRWD3 mutants, the increased H3.3 disrupts gene expression, dendritic morphogenesis, and sensory organ differentiation. Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations. Replication-independent deposition of histone H3.3 variant by the HIRA/YEM complex is a prominent nucleosome replacement mechanism affecting gene transcription, especially in postmitotic neurons. Our findings thus indicate that restricting histone H3.3 deposition through HIRA/YEM complex is the mechanism underlying dBRWD3-mediated transcription regulation. Our data suggest that uncontrolled deposition of H3.3 negatively affects gene transcription, implying that dBRWD3 promotes Wg signaling via negatively regulating the amount of histone H3.3 on Wg signaling target loci. Our work thus establishes a previously unknown negative regulation on H3.3 that is essential for gene expression and advances our understanding of BRWD3-dependent intellectual disability. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T03:38:07Z (GMT). No. of bitstreams: 1 ntu-104-D97448009-1.pdf: 15954306 bytes, checksum: f18e177b645285a7af87f2dbffd247e2 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | TABLE OF CONTENTS 口試委員審定書................................................................................................................i 誌謝...................................................................................................................................ii 中文摘要..........................................................................................................................iii 英文摘要..........................................................................................................................iv CHAPTER 1 INTRODUCTION 1.1 dBRWD3 and intellectual disability............................................................................1 1.1.1 Intellectual disability – an overview.....................................................................2 1.1.2 Intellectual disability – genetic analysis...............................................................4 1.1.3 Intellectual disability related to the epigenome....................................................6 1.2 The structure of chromatin...........................................................................................8 1.2.1 nucleosome and histone code theory....................................................................8 1.2.2 nucleosome in replication...................................................................................10 1.2.3 nucleosome in transcription................................................................................11 1.2.4 nucleosome in DNA repair..................................................................................13 1.3 The histone variant, the H3.3.....................................................................................16 1.3.1 The deposition of H3.3.......................................................................................16 1.3.2 H3.3 in transcription...........................................................................................17 1.3.3 H3.3 in replication..............................................................................................18 1.3.4 H3.3 in DNA repair.............................................................................................19 1.4 Ubiquitin proteasome system – an overview.............................................................19 1.4.1 Cullin Ring E3 ligases – an overview.................................................................20 1.4.2 Cullin 4 organized E3 CRL4..............................................................................21 1.4.3 DCAFs, substrate receptors for CRL4................................................................22 1.4.4 CRL4 and epigenetic regulation.........................................................................23 CHAPTER 2 RESULTS 2.1 Expression of dominant negative mutant of Cul4 in wing/eye discs........................25 2.2 Genetic screening for potential substrate receptors of Cul4 in wing/eye development....................................................................................................................27 2.3 The Wingless/Notch downstream targets genes are affected by knockdown of substrate receptors...........................................................................................................28 2.4 The histone tail modifications are changed in dBRWD3 mutants.............................31 2.5 Genetic screening for chromatin proteins related to dBRWD3 in eye......................32 2.6 Characterizations of dBRWD3 in photoreceptor differentiation...............................36 2.7 The transcriptome analyses of dBRWD3 mutant brains............................................38 2.8 Identification of H3.3 as a suppressor of dBRWD3...................................................39 2.9 dBRWD3 negatively regulates HIRA/YEM–mediated H3.3 deposition..................42 2.10 Inactivation of YEM suppresses lethality and aberrant gene expression caused by dBRWD3 mutation...........................................................................................................43 CHAPTER 3 DISCUSSION AND CONCLUSION....................................................46 MATERIALS AND METHODS..................................................................................57 FIGURES AND TABLES.............................................................................................63 Figure 1. The CRL4 is required for Wg signaling...........................................................63 Figure 2. The expression of Wg downstream targets are affected in dominant negative Cul4-expressing wing discs.............................................................................................65 Figure 3. dBRWD3 is a putative DCAF for Cul4-mediated regulation of Wg signaling.67 Figure 4. Knockdown of two enhancer DCAFs or one suppressor DCAF from genetic screen for Cul4-KR-notched wings does not affect the expression of Sens....................69 Figure 5. Knockdown of dBRWD3 but not other DCAFs such as CG9945, CG3909 or CG8440 affects the expression of Sens...........................................................................71 Figure 6. The reporter activity of Dll-lacZ, Wg downstream target, was not affected in knockdown of two DCAFs, CG3909 or CG9945...........................................................73 Figure 7. The reporter activity of Notch downstream target, E(spl)m8-lacZ, was slightly decreased but another Notch downstream target, Cut, was not altered in dominant negative Cul4-expressing wing discs...............................................................................75 Figure 8. The expression of Notch and Wg signaling downstream targets requires dBRWD3..........................................................................................................................77 Figure 9. dBRWD3 may regulate Wg signaling at the level downstream to Armadillo..79 Figure 10. dBRWD3 is required for expression levels of H3K9 di-, tri-methylation and H3K27 di-, tri-methylation..............................................................................................81 Figure 11. dBRWD3 is required for expression levels of H3K9, H3K27, H3K56, pan-H3 and pan-H4 acetylation....................................................................................................83 Figure 12. Genetic modifiers for dBRWD3-RNAi induced rough eye phenotype...........85 Figure 13. Slimb negatively regulates the levels of H3K9me3 via controlling the protein level of H3K9 methyltransferase, Su(var)3-9..................................................................87 Figure 14. dBRWD3 regulates the levels of H3K9me3 does not through controlling the protein level of slimb or Su(var)3-9................................................................................89 Figure 15. dBRWD3 is required for expressions of neuronal genes...............................91 Figure 16. dBRWD3 is required for the differentiation of photoreceptors......................93 Figure 17. slimb acts a suppressor for dBRWD3 in expression of neuronal genes..........95 Figure 18. Binding to DDB1 in CRL4 complex is essential for dBRWD3 in regulation of gene expression...........................................................................................................97 Figure 19. Dendritic morphogenesis and arista development in dBRWD3 depleted animals.............................................................................................................................99 Figure 20. dBRWD3 negatively regulates the amount of H3.3......................................101 Figure 21. dBRWD3 negatively regulates the chromatin-bound H3.3...........................103 Figure 22. dBRWD3 regulates gene expression by limiting H3.3 level on selective regions of chromatin......................................................................................................105 Figure 23. dBRWD3 regulates the development of nervous system through controlling H3.3 levels.....................................................................................................................107 Figure 24. HIRA/YEM rather than Dlp/XNP complex contributes to phenotypes in dBRWD3 knockdown eyes.............................................................................................109 Figure 25. dBRWD3 regulates H3.3 level in a HIRA/YEM dependent mechanism and dBRWD3 does not regulate protein levels of HIRA or YEM........................................111 Figure 26. dBRWD3 regulates neuronal genes through HIRA/YEM............................113 Figure 27. yem mutation suppresses nuclear migration and cytoskeleton defects in dBRWD3 mutant............................................................................................................115 REFERENCES............................................................................................................123 APPENDIX...................................................................................................................134 | |
| dc.language.iso | en | |
| dc.subject | 智能障礙 | zh_TW |
| dc.subject | 組蛋白 | zh_TW |
| dc.subject | BRWD3 | en |
| dc.subject | YEM | en |
| dc.subject | Intellectual Disability | en |
| dc.subject | Histone H3.3 | en |
| dc.subject | HIRA | en |
| dc.title | dBRWD3在果蠅發育上的分子機制 | zh_TW |
| dc.title | Molecular mechanism of dBRWD3 in Drosophila development | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 阮麗蓉,皮海薇,譚賢明,李秀香,潘俊良 | |
| dc.subject.keyword | 組蛋白,智能障礙, | zh_TW |
| dc.subject.keyword | BRWD3,HIRA,Histone H3.3,Intellectual Disability,YEM, | en |
| dc.relation.page | 141 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-03-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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