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研究生:蔡松華
研究生(外文):Evangelyn-C. Dominguez
論文名稱:奈米基材促進神經幹細胞生長分化之DNA甲基化模式研究
論文名稱(外文):DNA Methylation Patterns Behind the Growth and Differentiation of Neural Stem Cells on Different Fibrous Matrices
指導教授:陳中庸陳中庸引用關係金亭佑
指導教授(外文):Chung-Yung ChenTing-Yu Chin
學位類別:碩士
校院名稱:中原大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:113
中文關鍵詞:DNA 甲基化神經幹細胞分化
外文關鍵詞:DNA methylationNeural stem cell differentiation
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神經幹細胞分化在許多的應用中提供了廣泛且多樣的選擇,例如細胞治療或是基因治療,因此要全面的了解神經幹細胞內部的機制,我們必須由基因的層次上開始探討。表觀遺傳學涵蓋了很多方面,例如在不改變基因序列的情況下進而改變基因的表現或是調控神經幹細胞在分化成各種不同類型細胞時大部分的機轉,因此在神經幹細胞的機轉中闡明表觀遺傳調控的規則是很重要的,這個實驗的目的是為要找出在神經幹細胞於不同的基材中分化時,有哪些相關的機制涉及表觀遺傳的修飾調控;基因的表現與不表現分別在未分化和分化的細胞中將被經由篩選揭示出與分化相關的功能與路徑。為了這個目的,從培養在POMA的奈米材料上的細胞和神經幹細胞中純化出去氧核醣核酸,並且經由亞硫酸氫鈉處理、USER酵素的作用反應、生物素的標記、切口的接合、使用生物素來分離甲基化及未甲基化的去氧核醣核酸,再經adapter接合反應、PCR選擇性抑制雜交、TA-選殖以及選殖插入片段的分析和最後的基因序列定序。透過 Gene Set Toolkit (Gestalt) database 找出 12 個與分化相關的基因,其中有 6 個基因已被文獻報導過 (F2R, KIF5C, NCAM2, RB1, FZR1, and ZEB1),有4個基因被視為候選基因 (TIAM1, DCC, SLCO4C1, TCL1A),而有 2 個基因被預測可能成為候選基因 (USH1C, ZMIZ1)。另一方面來說,經由 DAVID資料庫有7個基因被鑑別為與分化相關;其中有4個基因已被證實 (HCN1, DMD, KIF5C, NCAM2),1個為候選基因 (DCC),1個基因被預測與分化有關 (USH1C),以及有1個基因尚未被證實涉及分化反應 (CNTNAP4, contactin associated protein-like 4)。只有 KIF5C、 NCAM2、 DCC、 USH1C 和 DMD 基因是同時經由兩個生物資訊工具證實的。利用 Pathway Interaction Database (PID),將上述基因之間的相關性於生理路徑中呈現出來。Netrin-mediated 訊息傳遞路徑被懷疑可能參與神經幹細胞的分化,因為經由Gestalt 和DAVID證實DCC基因是包含在這兩個路徑當中。基因甲基化的辨別確認了培養在POMA基質並用dbcAMP處理的神經幹細胞已成功分化,某些神經特異基因像是 KIF5C 和 ELMO1經由DNA甲基化的方式被關閉造成第七天時,細胞型態轉成神經膠細胞,證明了星狀細胞分化經這些基因調控的可能性。


The differentiation of neural stem cells offers a wide variety of options in many applications, such as in cellular therapy and gene therapy; hence to fully understand the inner machinery of neural stem cells, we have to begin at the genetic level. Epigenetics, which encompasses changes in gene expressions without imposing alterations in the genetic sequence, governs most of the mechanisms that lead to neural stem cell differentiation into different types of cells. Therefore it is important to elucidate its roles in the neural stem cell machinery. The objective of this study is to identify epigenetic modifications to discover related mechanisms involved in neural stem cell differentiation. Genes expressed and unexpressed in both undifferentiated and differentiated cells will be screened to reveal relevant pathways and functions associated with differentiation. For this purpose, genomic DNA extracted from cells cultured on different biomaterials and NSCs were subjected to a series of steps beginning with Bisulfite treatment, USER enzyme reaction, biotinylation, ligation of nicks, separation of unmethylated and methylated DNA using Streptavidin, Mung Bean Nuclease reaction, adapter ligation, PCR seletive suppression hybridization, TA cloning, clone insert analysis, and finally gene sequencing. Twelve differentiation genes were identified by Gene Set Toolkit (Gestalt) database: 6 confirmed by literuature reports (F2R, KIF5C, NCAM2, RB1, FZR1, and ZEB1), 4 considered as candidate (TIAM1, DCC, SLCO4C1, TCL1A), and 2 predicted to be candidates (USH1C, ZMIZ1). On the other hand, 7 genes were identified by DAVID to be differentiation-related; 4 were confirmed genes (HCN1, DMD, KIF5C, NCAM2), 1 candidate gene (DCC), 1 predicted (USH1C), and one whose involvement in differentiation is not yet fully explored (CNTNAP4, contactin associated protein-like 4). Only KIF5C, NCAM2, DCC, USH1C, and DMD were validated by both Bioinformatics tools. Based on the Pathway Interaction Database (PID), some of these genes are indirectly related by pathways. Of the identified pathways, netrin-mediated signaling and pathways in cancer may be associated with neural stem cell differentiation as DCC, which was confirmed by Gestalt and DAVID, is involved in them. Identification of methylated genes confirmed the successful differentiation of NSCs on POMA substrate with dbcAMP treatment, while silencing of neuron-specific genes such as KIF5C and ELMO1 through methylation supported the possibility of astrocyte differentiation, as evident from the morphology of cells at Day 7, which showed early glial-like features.


中文摘要 ……………………………………………………………….……………..I
ABSTRACT………………………………………………………………………….III
ACKNOWLEDGEMENT…………………………………………………………….V
CONTENTS………………………………………………………………………...VII
LIST OF FIGURES…………………………………………………………………...X
LIST OF TABLES…………………………………………………………………..XII
INTRODUCTION…………………………………………………………………….1
1.1 Epigenetics………………………………………………………………...2
1.1.1 Histone Modification…………………………………………………...2
1.1.2 MicroRNAs…………………………………………………………….3
1.1.3 DNA Methylation………………………………………………………4
1.2 Neural Stem Cells………………………………………………………….9
1.2.1 The Origin and Nature of NSCs in vitro……………………………...10
1.2.2 Behavior and Culturing of NSCs in vitro……………………………..12
1.2.3 Neural Stem Cell Differentiation……………………………………..15
1.2.3.1 Neurotransmitters and Neuropeptides……………………..15
1.2.3.2 Signaling Pathways………………………………………..16
1.2.4 Epigenetic Regulation in Neural Stem Cell Differentiation…………..21
1.2.4.1 DNA Methylation and CpG Dinucleotides………………..21
1.2.4.2 Histone Modification………………………………………23
1.3 Aims of the Study………………………………………………………...25
MATERIALS and METHODS………………………………………………………26
2.1 Research Strategy………………………………………………………...27
2.2 Electrospun Fibrous Matrices…………………………………………….27
2.3 Cell Culture and Genomic DNA Extraction……………………………...27
2.4 Bisulfite Treatment (Qiagen® Epitect Bisulfite)………………………….29
2.5 USERTM Enzyme NEB® Treatment………………………………………30
2.5.1 Materials………………………………………………………………30
2.5.2 USERTM Enzyme NEB® Reaction……………………………………30
2.6 Biotin-14-dCTP (InvitrogenTM) Labeling………………………………...31
2.6.1 Materials……………………………………………………………....31
2.6.2 DNA Polymerase I (E. coli) NEB® Reaction…………………………31
2.7 Ligation of Nicks by T4 DNA Ligase (TAKARA)……………………..32
2.8 Separation of Biotin-labeled DNA by Dynabeads® Streptavidin
(InvitrogenTM)…………………………………………………………….32
2.9 Mung Bean Nuclease NEB® Treatment………………………………….33
2.9.1 Mung Bean Nuclease NEB® Reaction………………………………..33
2.10 Adapter Ligation………………………………………………………...34
2.10.1 Materials……………………………………………………………..34
2.10.2 Adapters……………………………………………………………..34
2.10.3 Double-stranded Adapter Working Solution………………………...35
2.10.4 Adapter Ligation……………………………………………………..35
2.11 PCR Selective Suppressive Hybridization (PSSH)……………………..35
2.11.1 Materials……………………………………………………………..35
2.11.2 Suppression Hybridization…………………………………………..36
2.11.3 Primary PCR Selection………………………………………………36
2.11.4 Secondary PCR Selection……………………………………………37
2.12 TA Cloning………………………………………………………………37
2.12.1 Preparation of Electrocompetent Cells………………………………37
2.12.2 TA Cloning…………………………………………………………..38
2.12.3 Electroporation………………………………………………………38
2.12.3.1 Materials………………………………………………….38
2.12.3.2 Transformation of E. coli by Electroporation (BIO-RAD®
MicroPulser)……………………………………………………….39
2.13 Clone Insert Analysis by PCR…………………………………………..40
2.14 Electrophoresis………………………………………………………….40
2.14.1 Materials……………………………………………………………..40
2.15 Sequencing and Bioinformatics Analysis……………………………….41
RESULTS……………………………………………………………………………43
DISCUSSION……………………………………………………………………….62
4.1 Principle of PCR Selective Suppressive Hybridization (PSSH)…………63
4.2 Neural Stem Cell Growth on Various Materials………………………….64
4.3 Epigenetics Results………………………………………………………66
REFERENCES………………………………………………………………………71
APPENDIX………………………………………………………………………….81





LIST OF FIGURES

Figure 1.1 Epigenetics-miRNA regulatory circuitry…………………………………..4
Figure 1.2 Mechanism of DNA-methylation-mediated repression……………………6
Figure 1.3 CpG methylation…………………………………………………………...6
Figure 1.4 Targeting de novo DNA methylation………………………………………8
Figure 1.5 Schematic diagram of the adult rodent brain……………………………..11
Figure 1.6 Temporal development of NSCs in the SVZ of the cerebral cortex……...12
Figure 1.7 Different cell fates of neural stem cells as induced by different factors in vitro…………………………………………………………………………………...13
Figure 1.8 Schematic outline of the possible events during neural stem cell expansion in culture……………………………………………………………………………...14
Figure 1.9 Signaling pathways involved in neural stem cell differentiation………...16
Figure 1.10 Wnt signaling pathway………………………………………………….18
Figure 1.11 BMP signaling pathway…………………………………………………19
Figure 1.12 STAT3 signaling pathway……………………………………………….20
Figure 1.13 Shh signaling pathway…………………………………………………..20
Figure 2.1 Research strategy…………………………………………………………28
Figure 2.2 Schemes used for cell culture…………………………………………….28
Figure 2.3 PCR Selective Suppressive Hybridization (PSSH)………………………29
Figure 3.1 TEOS-based materials……………………………………………………44
Figure 3.2 NSCs cultured on POMA for 7 days with or without dbcAMP (3.5cm dish)
......................................................................................................................................45
Figure 3.3 NSCs cultured on TEOS, PVA/TEOS, and PDL-coated glass for 5 days
………………………………………………………………………………………..47
Figure 3.4 Electrospun POMA in 10cm dish………………………………………...47
Figure 3.5 NSCs cultured on POMA and PDL for 7 days without dbcAMP………...47
Figure 3.6 NSCs cultured on POMA for 7 days (10cm) with and without drug……..49
Figure 3.7 Primary PCR after PSSH…………………………………………………50
Figure 3.8 Secondary PCR after PSSH………………………………………………51
Figure 3.9 Clone insert analysis by PCR……………………………………………..51
Figure 3.10 Bar graphs showing the number of genes involved in different processes (Gestalt)………………………………………………………………………………51
Figure 3.11 Enrichment analysis for Gene Ontology categories (Gestalt)…………...83
Figure 3.12 Chemokine signaling pathway (Gestalt)………………………………...84
Figure 3.13 Cell cycle pathway (Gestalt)…………………………………………….85
Figure 3.14 Regulation of actin cytoskeleton (Gestalt)………………………………86
Figure 3.15 Neuroactive ligand-receptor interaction (Gestalt)………………………87
Figure 3.16 Pathways in cancer (Gestalt)…………………………………………….88


LIST OF TABLES

Table 3.1 Genes directly associated with stem cell proliferation and differentiation..52
Table 3.2 Candidate genes indirectly involved in stem cell differentiation (from literature)……………………………………………………………………………..55
Table 3.3 Candidate genes predicted to be involved in stem cell proliferation and differentiation………………………………………………………………………...57
Table 3.4 Relationship between confirmed genes and candidate genes…….………..58
Table 3.5 Combined classification of relevant genes based on DAVID and Gestalt...60
Table 3.6 Gene Cluster 1: Neuronal development including differentiation and neuron projection morphogenesis (DAVID)……....................................................................89
Table 3.7 Gene Cluster 2: Cellular transport, including ion-gated channels, signaling and membrane transport…………………………………...........................................89
Table 3.8 Gene Cluster 3: Chromatin organization and transcription regulation…….91
Table 3.9 Gene Cluster 4: Cellular processes in the nucleus, including transcription regulation, RNA metabolic process regulation, nucleoplasm, DNA binding, and transcription………......................................................................................................91
Table 3.10 Gene Cluster 5: Cell cycle……………….……………………………….93
Table 3.11 Gene Cluster 6: Cellular components……………….……………………93
Table 3.12 Gene Cluster 7: Protein transport…………..…………………………….94
Table 3.13 Gene Cluster 8: Cellular organelles, enzymes, and cytoskeleton………..94
Table 3.14 Gene Cluster 9: Nucleotide binding………………………...……………95
Table 3.15 Gene Cluster 10: Ionic binding……………………………….………….96
Table 3.16 Gene Cluster 11: Membrane function……………………………………96
Table 3.17 Gene Cluster 12: Neurological system processes………...………………97
Table 3.18 Genes involved in cell differentiation (Gestalt).........................................97
Table 3.19 Genes involved in neuron projection morphogenesis……………………98

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