Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20321
DC FieldValueLanguage
dc.contributor陳全木zh_TW
dc.contributorChuan-Mu Chenen_US
dc.contributor.author沈志傑zh_TW
dc.contributor.authorShen, Chih-Jieen_US
dc.contributor.other生命科學系所zh_TW
dc.date2012en_US
dc.date.accessioned2014-06-06T07:13:23Z-
dc.date.available2014-06-06T07:13:23Z-
dc.identifierU0005-2208201211193400en_US
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dc.identifier.urihttp://hdl.handle.net/11455/20321-
dc.description.abstract在哺乳類的基因體中,去氧核醣核酸甲基化(DNA methylation)為主要上遺傳性修飾(epigenetic modification)之一,並調控著許多基因的重要功能表現。利用體細胞核轉置技術(somatic cell nuclear transfer technique; SCNT)所產生的哺乳動物常伴隨著妊娠或出生時的發育失敗風險,且其成功產製出活體複製動物的比例亦極為稀少。甚且成長至成體的複製動物也常有許多器官發育或遺傳上的變異,目前研究學者普遍歸咎這些原因可能為不恰當的上遺傳性修飾。單一親緣染色體表現之銘印基因(imprinted genes)是一群調控胚胎正常生長及發育的重要因子,本研究結果顯示在外表看似正常的複製動物基因體中,其銘印基因的預測差異性甲基化片段(putative differentially methylated regions; putative DMRs)仍然存在著許多異常甲基化修飾。吾人發現並鑑定出在豬及牛基因體中銘印基因之預測差異性甲基化片段的甲基化銘印模式在人工性核轉置過程是非常的不穩定;此等混亂的甲基化修飾現象,推測係略過正常精卵受精所需的再程序化作用(reprogramming process)所使然。已分化的體細胞其細胞核並沒有像生殖細胞一樣接受正常的再程序化作用,對一些已知的上遺傳修飾性位點達到正確位置及時間點上的移除,這些不恰當的親緣銘印性修飾資訊將被帶進複製動物的基因體中,因而影響基因的表現且引起非預期的病症。OPN及H19基因的甲基化調控片段是經由甲基親和性結合區(methyl-binding domain; MBD)蛋白所分離出來,這些片段並在複製豬耳朵組織的基因體中呈現異常甲基化的型態,吾人亦於OPN基因的啟動子中鑑定出可受甲基化調控之CpG雙核酸位點 (CpG 1, CpG 13, and CpG 20)。我們進一步利用差異性甲基化雜合晶片(differentially methylated hybridization chip: DMH chip)來篩選於複製動物基因體中有變異的甲基化DNA片段,於心臟、耳朵及睪丸組織中皆有其基因甲基化變異,其中有五個基因,包括:EXD3, PDZD4, MTMR7, IGF2R, 和PEG3等基因,業經成功篩選並評估具有預測性差異甲基化片段作為後續的分析。值得一提的是PEG3蛋白,由於在複製豬五號的睪丸呈現無精症(azoospermia),吾人以免疫組織染色法來分析於正常豬及複製豬五號的睪丸中,其PEG3, NFκB, β-catenin, 及E-cadherin蛋白的表現及分布位置,結果證明其中E-cadherin及β-catenin蛋白分別係分布於複製豬五號睪丸的生精細管管腔邊緣(正常豬則分布在睪丸生精細管管腔內部),而PEG3蛋白則分布在複製豬五號睪丸生精細管管腔內部(正常豬則分布在生精細管管腔外部及萊氏細胞中),目前已知PEG3的存在會造成β-catenin的降解,而E-cadherin在細胞膜上能促進精原母細胞(spermatogonia)的移動功能,同樣也會受到β-catenin的調控,因此吾人推測PEG3蛋白的分布位置及表現的異常,可能是導致生精作用不全之一原因。進一步研究完成鑑定豬隻基因體中,四個銘印基因的主要差異性甲基化區域,分別為INS和IGF2 (母源性染色體銘印基因)及H19和IGF2R (父源性染色體銘印基因)。甲基化異常之現象,包括:高度甲基化 (hypermethylation)及低度甲基化(hypomethylation);在複製豬的基因體中其甲基化程度之變異比例,分別為:H19 (45% vs. 30%), IGF2 (40% vs. 0%), INS (50% vs. 5%), 和IGF2R (15% vs. 45%);在複製牛基因體中者,則為:H19 (0% vs. 29%), IGF2 (21% vs. 29%), 和XIST (7.9% vs. 7.9%)。目前對於大型哺乳類動物的銘印基因之研究報告甚少,本研究係透過甲基化銘印模式的分析,顯示複製豬及牛的銘印基因的甲基化異常的確是經常發生的現象。為謀瞭解此等甲基化修飾異常是否擴及其他染色體區域,進一步研究且完成分析四個衛星基因座(Satellite loci),包括:Satellite I, Satellite II, VNTR, 及Art2等,結果證明其甲基化差異性不大,研究顯示在銘印基因調控區及衛星片段調控區有著不同的甲基化調控機制。更進一步藉由即時定量聚合酶連鎖反應,觀察銘印基因在複製豬NT-6組織上的表現,結果顯示在複製豬的肝臟、靜脈、耳朵、皮膚及子宮等組織中,其IGF2及H19的表現分別均有過量表現的異常情形。總結前述試驗說明了即使複製成功且能長大為成體的豬或牛隻,其基因體中保留了在胚胎時期所獲得的異常甲基化銘印模式,雖然避免於分娩前即死亡的命運,但是此等異常甲基化的銘印模式,的確足以影響其出生後之存活時間或成體後呈現病徵之情事。總結本研究結果,證明在複製動物的產製過程中仍存在關於健康及導致非預期病症的風險,深入瞭解彼等在複製動物產製過程中銘印基因的異常甲基化變動並加以校正,顯然係未來改善核轉置動物複製技術的一個重要環節。zh_TW
dc.description.abstractDNA methylation is a major epigenetic modification found in mammalian genomes and it regulates crucial aspects of gene functions. Mammal cloning by somatic cell nuclear transfer (SCNT) often results in gestational or neonatal failure with only a few percentage of manipulated embryos producing live births. Many of the cloned embryos that survive to term succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. The uniparentally expressed imprinted genes control the development of embryos. This study has shown the aberrant putative differentiated methylation regions (DMRs) of imprinted genes existed in the genome of cloned animal, even their appearance looks like normal. In this study, we firstly defined the several putative DMRs of imprinted genes in cloned porcine and bovine genomes. The putative DMRs of imprinted genes are vulnerable during somatic cell nuclear transfer (SCNT) process. The skipping of the reprogramming process happened in cloning animals by nuclear transfer of somatic cells may cause the inappropriate methylation patterns. The differentiated somatic cells, unlike germ cells, do not back to the necessary reprogramming process to erase the epigenetic markers correctly and timely. These abnormal modifications could affect the expression of genes and cause the unexpected pathologies. The OPN and H19 were identified by the multimeric methyl-binding domain (MBD) protein pull down assay. We also demonstrated three CpG sites (CpG1, CpG13, and CpG20) which regulate the OPN transcription by their DNA methylation status. In cloned pigs, these OPN and H19 genes showed aberrant methylation patterns in their ear tissues. Furthermore, differentially methylated hybridization chip (DMH chip) was also performed to screen the aberrant methylated DNA elements in cloned animals. Either hypermethylation or hypomethylation frequently appeared in the tissues of cloned animals. Five genes, EXD3, PDZD4, MTMR7, IGF2R, and PEG3 were selected for further study. Especially, the PEG3 with aberrant methylation status was selected from cloned pig CP5 testis with azoospermia phenomenon. The immunohistochemistry (IHC) staining of PEG3 showed the extremely different distribution in testis between wild-type (WT) and CP5 pigs. The PEG3 interacts with NF-κB, β-catenin, and E-cadherin. The data showed that CP5 testis lacked of the E-cadherin expression inside testicular cord. The aberrant location of PEG3 expression may affect the maturation of spermatogonia through the down-regulated β-catenin and E-cadherin. Connectively, we identified four DMRs of imprinted genes in the wild-type pig genomes, including two maternal imprinted loci (INS and IGF2) and two paternal imprinted loci (H19 and IGF2R). Aberrant DNA methylation phenomenon, either hypermethylation or hypomethylation, commonly appeared in H19 (45% vs. 30%), IGF2 (40% vs. 0%), INS (50% vs. 5%), and IGF2R (15% vs. 45%) imprinted loci, in cloned pigs and also found in cloned bovine genomes: H19 (0% vs. 29%), IGF2 (21% vs. 29%), XIST (7.9% vs. 7.9%). Our data also revealed that aberrant methylation frequently occurred in imprinted genes, but not satellite loci, Satellite I, Satellite II, VNTR, and Art2, in cloned bovine. It indicated that the methylation between imprinted genes and satellite loci is regulated by different mechanisms. Furthermore, quantitative RT-PCR was applied to assess the expression of these imprinted genes in the cloned bovine NT-6. We found that IGF2 and H19 extremely overexpressed in the liver, vein, ear, skin, and uterus of the NT-6 bovine. In conclustion, even the successful produced of cloned swine and bovine fortunately avoid the preneonatal or postnatal death, the perturbation and intervention of mehtylation in imprinted genes still exists. It perhaps may be the reasons of adult pathologies and short life occurred in cloned animals. Here, we provided the results that the cloned animals still have the several risks of health and unexpected defects. Finding and correcting the aberrant pattern of imprinted genes after SCNT would offer insights into the improvement in future cloning animal technique.en_US
dc.description.tableofcontents封面內頁 簽名頁 授權書 致謝...........................................................................................................................................ⅰ 中文摘要...................................................................................................................................ⅱ Abstract...................................................................................................................................ⅳ Content...................................................................................................................................ⅶ Table content........................................................................................................................xiii Figure content........................................................................................................................xv Chapter 1. General Introduction: The conflict between genomic imprinting mechanism and cloning technique..................................................................................1 1-1 Genomic imprinting......................................................................................................1 1-1-1 Discovery of imprinting gene...................................................................................1 1-1-2 Evolution of genomic imprinting.............................................................................2 1-2 Epigenetic mark.............................................................................................................7 1-2-1 DNA methylation..........................................................................................................7 1-2-2 DNA methyltransferase (Dnmt)..............................................................................11 1-2-3 The physiological functions of 5-hydroymethylcytosine....................................11 1-2-4 The mechanism of chromatin modification.........................................................13 1-2-5 Methyl CpG binding proteins and transcriptional repression..........................15 1-3 Dynamic reprogramming process of genomic imprints......................................15 1-3-1 Erasion of the methylation markers.....................................................................16 1-3-2 Establishment of the methylated markers..........................................................16 1-3-3 Maintenance of the methylation.............................................................................18 1-4 Loss of regulation in imprinted genes....................................................................18 1-4-1 The genetic diseases caused by misregulation of imprinted genes...........19 1-4-2 Imprinting and cancer.............................................................................................21 1-4-3 Role of imprinting genes in fetal development and placental function.........21 1-4-4 Imprinting defects affected by assisted reproductive technology..................23 1-4-5 Imprinting defects in cloned animals..................................................................24 1-5 Imprinting regulation..................................................................................................26 1-5-1 Promoter methylation.............................................................................................26 1-5-2 Antisense transcripts.............................................................................................26 1-5-3 Boundaries of insulator..........................................................................................28 1-5-4 Imprinting of non-coding RNA and siRNA..........................................................28 1-5-5 Bipartite imprinting center......................................................................................29 1-6 How to screen imprinting genes?.............................................................................29 1-7 DNA methylation detection methodology................................................................33 1-7-1 The crucial physiological role of methylation change.......................................33 1-7-2 The detection method of the total cell genome amount of methylation percentage...........................................................................................................................33 1-7-3 The estimation of methylation percentage in a single gene...........................34 1-7-4 The detection methods of multiple gene of methylation profiles..................36 1-7-5 The detection methods of genome wide genes of methylation patterns....38 1-8 The major purpose of this study.............................................................................40 1-9 Specific Aims...............................................................................................................41 1-9-1 Aim I: Developing methods for screening methylated regulating regions of cloned porcine genome by methyl-binding domain (MBD) protein..........................41 1-9-2 Aim II: Developing high throughput screening for aberrant methylated regions of cloned porcine with differentially methylated hybridization (DMH) chip........................................................................................................................................41 1-9-3 Aim III: The verification of putative DMRs of selected imprinted genes in cloned porcine genomes..................................................................................................42 1-9-4 Aim IV: Studying the mechanism of methylation-controlled transcription of OPN that identified by ChIP assay with MBD................................................................42 1-9-5 Aim V: Confirmation of the differentially methylated statuses between global satellite loci and imprinted genes in cloned bovine genomes................................43 Chapter 2 Applications methyl-binding-domain (MBD) protein for identification of hypermethylated genes in cloned porcine...................................................................44 2-1 Brief introduction........................................................................................................44 2-2 Materials and Methods.............................................................................................46 2-2-1 Expression and purification of multimeric MBD protein.................................46 2-2-2 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE)..46 2-2-3 Electrophoresis mobile shift assays (EMSA)...................................................46 2-2-4 Cell culture.............................................................................................................49 2-2-5 Immunocytochemistry with multimeric MBDs in fixed cells..........................49 2-2-6 Global methylation detection.............................................................................49 2-2-7 Chromatin immunoprecipitaion (ChIP) assay with 3x MBD.........................50 2-2-8 Methylation specific-PCR....................................................................................50 2-2-9 Statistical analysis...............................................................................................53 2-3 Results.......................................................................................................................53 2-3-1 Characteristics of constructed multimer MBD proteins................................54 2-3-2 Detection of methylated DNA by multimer MBD proteins in vitro..................54 2-3-3 Binding activity of multimeric MBD to methylated CpG sites in fixation fibroblast cells................................................................................................................55 2-3-4 The methylation status comparison in cloned porcine with 3xMBD............55 2-3-5 The methylation status comparison in lung cancer cells with 3xMBD..........60 2-4 Discussion...................................................................................................................64 Chapter 3. Using differentially methylated hybridization (DMH) chip to screen imprinted genes in cloned porcine genomes..............................................................66 3-1 Brief introduction........................................................................................................66 3-2 Materials and Methods...............................................................................................67 3-2-1 Extraction of genomic DNA.....................................................................................67 3-2-2 DMH chip (differentially methylated hybridization microarray gene chip)......68 3-2-3 Sodium bisulfite modification................................................................................76 3-2-4 Combined bisulfite restriction analysis (COBRA)..............................................77 3-2-5 Sodium bisulfite sequencing................................................................................78 3-2-6 The primer designation and selection of CpG island......................................78 3-2-7 Pathological histology.............................................................................................78 3-2-8 IHC staining..............................................................................................................83 3-3 Results........................................................................................................................83 3-3-1 Screening the samples for DMH chip by H19 DMR methylation status.....83 3-3-2 The methylation change of the cloned pigs genome detected by the DMH microarray..........................................................................................................................84 3-3-3 The hypermethylated genes selected from overlapped gene pool (CP12 ear, CP11 heart, and CP5 testis.............................................................................................89 3-3-4 Screening the sequence of candidate genes identified from DMH chip of three tissues, CP12 ear, CP11 heart, and CP5 testis...............................................87 3-3-5 IPA analysis of EXD3, PDZD4, MTMR7, IGF2R, and PEG3...............................87 3-3-6 Searching of CpG islands of EXD3, PDZD4, MTMR7, IGF2R, and PEG3.....90 3-3-7 Methylation analysis of EXD3, PDZD4, MTMR7, IGF2R, and PEG3 by COBRA and bisulfite sequencing...................................................................................................90 3-3-8 The prediction of transcriptional factors in the sensitive CpG sites of EXD3, PDZD4, MTMR7, IGF2R, and PEG3.............................................................................91 3-3-9 The IHC analysis of CP5 testis tissue...............................................................92 3-4 Discussion................................................................................................................105 Chapter 4. Differential differences in methylation status of putative imprinted genes in cloned porcine genome............................................................................................108 4-1 Brief Introduction......................................................................................................108 4-2 Materials and Methods...........................................................................................110 4-2-1 Tissue sample collection of cloned and wild-type sows.............................110 4-2-2 Isolation of genomic DNA................................................................................110 4-2-3 Southern blot combined methylation-sensitive enzyme digestion............111 4-2-4 Methylation-specific PCR (MS-PCR)...............................................................114 4-2-5 Methylation analysis by COBRA..........................................................................114 4-2-6 Bisulfite sequencing............................................................................................115 4-2-7 RNA isolation and semi-quantitative RT-PCR..............................................115 4-2-8 The analysis and quantification of methylation changes.............................116 4-3 Results...................................................................................................................116 4-3-1 Identification of putative DMRs of imprinted genes in the porcine genome.............................................................................................................................116 4-3-2 Aberrant methylation of H19 gene in various tissues from cloned pigs....117 4-3-3 Aberrant methylation of IGF2 gene in various tissues from cloned pigs...122 4-3-4 Aberrant methylation of INS gene in various tissues from cloned pigs....126 4-3-5 Aberrant methylation of IGF2R gene in various tissues from cloned pigs.128 4-3-6 Compared with the methylation status percentage in paternal and maternal expression gene derived from different germ layer of cloned pigs.....................128 4-3-7 The mRNA expression and methylation analysis of putative DMRs demonstrated by 5-aza-dc treated pig ear fibroblast cell.......................................131 4-3-8 The methylation status of parental allele during various tissues derived from cloned pigs in different germ layers.........................................................................131 4-3-9 The correlations between the aberrant methylation of DMR in the imprinted genes and the birth body weight, death body weight, survival rate and major defects............................................................................................................................134 4-3-10 Comparison of the methylation in multiple genes in various tissues....135 4-4 Discussion................................................................................................................139 Chapter 5. OPN promoter controlled by DNA methylation: Aberrant DNA methylation in cloned porcine genome..........................................................................................146 5-1 Brief introduction.....................................................................................................146 5-2 Materials and Methods............................................................................................149 5-2-1 CpG island prediction..........................................................................................149 5-2-2 Cell culture.............................................................................................................149 5-2-3 5-Aza-dc treatment..............................................................................................149 5-2-4 Quantitative real-time PCR.................................................................................149 5-2-5 Methylation analysis by COBRA.........................................................................149 5-2-6 Methylation specific-PCR....................................................................................150 5-2-7 Plasmid constructs...............................................................................................150 5-2-8 Transient transfection and luciferase assay....................................................152 5-2-9 In vitro methylation of the OPN promoter region..............................................153 5-2-10 Electrophoresis mobile shift assays..............................................................153 5-2-11 EMSA probe preparation.................................................................................154 5-2-12 Nuclear protein extraction.............................................................................154 5-2-13 Protein/Probe binding.....................................................................................155 5-2-14 Electrophoresis mobile shift assay (EMSA)..................................................155 5-2-15 Reagents and Buffers used in EMSA............................................................156 5-3 Results......................................................................................................................157 5-3-1 Analysis of the change of DNA methylation and RNA expression of OPN in cloned pig various tissues..........................................................................................157 5-3-2 The increasing of OPN mRNA and decreasing methylation of OPN promoter was observed in the pig ear fibroblast cell treated with 5-aza-dc........................157 5-3-3 Bisulfite sequencing analysis of the methylation profile among the front CpG sites of OPN promoter in cloned pigs......................................................................157 5-3-4 The transcription activity of OPN promoter was affected by itself methylation status.................................................................................................................................161 5-3-5 Methylation in CpG 1, CpG 13 and CpG 20 of OPN promoter block the binding access of transcription factors.....................................................................166 5-4 Discussion...............................................................................................................169 Chapter 6. Imprinted genes and satellite are differentially methylated loci in cloned bovine genomes.............................................................................................................173 6-1 Brief introduction.......................................................................................................173 6-2 Materials and Methods........................................................................................175 6-2-1 Search putative DMRs on bovine H19 and IGF2............................................175 6-2-2 Samples collection of cloned bovine..............................................................175 6-2-3 Cell culture and 5-aza-dc treatment.................................................................178 6-2-4 Isolation of genome DNA....................................................................................178 6-2-5 Methylation analysis by COBRA..........................................................................179 6-2-6 Bisulfite sequencing..........................................................................................179 6-2-7 RNA isolation and RT-PCR.................................................................................179 6-2-8 Statistical analysis................................................................................................180 6-3 Results......................................................................................................................182 6-3-1 Aberrant methylation profiles of the IGF2, XIST, and H19 imprinted genes in cloned bovine.................................................................................................................182 6-3-2 Confirmation of methylation changes in putative DMR sequences of the imprinted genes.............................................................................................................182 6-3-3 Distribution of methylation levels of imprinted and satellite genes in various tissues of each individual cloned bovine..................................................................185 6-3-4 The aberrant expression of imprinting genes in NT-6 tissues.....................187 6-3-5 Demethylation treatment of bovine ear fibroblast cells is correlated with RNA expression............................................................................................................................187 6-3-6 The physiological defects and tissues section of cloned bovine NT-6......191 6-4 Discussion.................................................................................................................194 Chapter 7. Discussions and Conclusions...................................................................201 7-1 General discussion...................................................................................................201 7-1-1 Insufficiency of genome sequence in big mammals and the limitation of gene analysis..............................................................................................................................203 7-1-2 Using human DMH chip instead of pig DMH chip..........................................203 7-1-3 The multimeric MBD binding affinity is best at trimer form for methylated DNA regions studying.............................................................................................................204 7-1-4 The aberrant methylation profiles of imprinted genes in cloned pig genome..............................................................................................................................204 7-1-5 The deeply looking of OPN gene regulated by DNA methylation.............206 7-1-6 The differentially difference methylation profiles between imprinted genes and satellite locus in cloned bovine......................................................................................207 7-1-7 The imprinted H19-IGF2 have no obvious coordinate effects in this study..208 7-1-8 The correlation between DNA methylation and RNA expression of imprinted gene...................................................................................................................................209 7-1-9 Comparison of the aberrant methylation patterns between cloned pig and bovine genome in this study.............................................................................................210 7-1-10 The possible correlated genes to these aberrant methylation phenomenon and pathologies...................................................................................................................213 7-1-11 More works need to do for improving the cloning efficiency.......................215 7-2 Conclusion remarks................................................................................................217 Reference............................................................................................................................220 Appendix...............................................................................................................................244 Acknowledge.......................................................................................................................250 作者小傳...............................................................................................................................251 Table content Table 1-1. Known imprinted genes..................................................................................4 Table 1-2. Alternative disorders of imprinted genes deficiency................................20 Table 1-3. Biological functions of imprinted genes.....................................................23 Table 1-4. Low efficiency of live/born clones................................................................26 Table 1-5. Developmental and tissue specific regulation of imprinted macro ncRNAs.................................................................................................................................33 Table 1-6. The information of cloned pigs and bovines used in this study..............42 Table 2-1. The primer sets of MS-PCR and ChIP assay.............................................54 Table 3-1. The hypermethylated and overlapped candidate genes of three tissues.....................................................................................................................................81 Table 3-2. The candidate genes of Copy5 testis...........................................................82 Table 3-3. COBRA primer sets of analyzed genes in putative DMRs........................83 Table 3-4. Prediction transcription factors binding sites in analyzed aberrant methylated CpG sites of candidate genes....................................................................98 Table 4-1. Body weight, survival time, and aberrant methylation status of imprinted genes in wild-type and of cloned pigs............................................................................116 Table 4-2. Experimental primer sets designation used in this study.......................117 Table 4-3. The methylation status of maternally imprinted genes in three germ layers.................................................................................................................................134 Table 4-4. The methylation status of paternally imprinted genes in three germ layers................................................................................................................................134 Table 4-5. The methylation status of both maternally and paternally imprinted genes in three germ layers............................................................................................................134 Table 4-6. Row data of methylation percentage in IGF2 genes of four cloned pigs and three wild-type pigs....................................................................................................141 Table 4-7. Row data of methylation percentage in IGF2R genes of four cloned pigs and three wild-type pigs..................................................................................................141 Table 4-8. Row data of methylation percentage in INS gene four cloned pigs and three wild-type pigs........................................................................................................141 Table 4-9. Row data of methylation percentage in H19 gene of four cloned pigs and three wild-type pigs............................................................................................................142 Table 4-10. The comparison of all samples of four genes in four cloned pigs...142 Table 4-11. The methylation status of all samples of each genes in each cloned pig........................................................................................................................................142 Table 4-12. The methylation status of all samples of all genes in each cloned pig.......................................................................................................................................142 Table 4-13. The methylation status of each genes in all samples....................142 Table 5-1. The annealing primers of EMSA probes..................................................155 Table 6-1. Summary of the life span and defective features of in different cloned bovine individuals................................................................................................................181 Table 6-2. Primer sets designed for COBRA and real-time PCR experiments.....185 Table 6-3. DNA methylation percentages of IGF2, XIST, and H19 imprinting genes and repetitive sequences after treated with different concentrations of 5-aza-dc in NT-6 cloned bovine ear fibroblast cells...........................193 Table 6-4. Summary of epigenetic aberrance, gene expression disorder, and clinical pathological data in cloned bovines................................................................203 Table 6-5. Methylation percentage of different imprinting genes and repetitive sequence in each individual (by COBRA data)...........................................................204 Table 7-1. Key pathological phenotypes reported in cloned animals...................223 Figure content Figure 1-1. Life cycle of methylation imprints..................................................................3 Figure 1-2. The schematic diagram of the location of imprinted genes on chromosome.........................................................................................................................5 Figure 1-3. DNA methylation in mammals occurs in the CpG dinucleotide...........10 Figure 1-4. Models depicting the relationship between DNA methylation, histone deacethylation, and histone methylation........................................................................15 Figure 1-5. Methylation reprogramming in the germ line and embryo....................16 Figure 1-6. The simple concept of genomic imprinting..............................................17 Figure 1-7. The alternative regulation mechanisms of imprinted genes...............30 Figure 1-8. Two mouse imprinted gene clusters containing a regulatory macro ncRNA.................................................................................................................................31 Figure 1-9. Regulation of imprinted regions by MeCP2................................................32 Figure 1-10. Schematic flowchart showed the preparation of amplicon for DMH..40 Figure 2-1. The structure of multimeric MBD proteins................................................49 Figure 2-2. Flow chart of ChIP assay with 3xMBD purified protein.............................53 Figure 2-3. Multimerization of 3xMBD protein increases the affinity and capacity for methylated DNA element...........................................................................................57 Figure 2-4. The sensitive of multimeric MBD proteins stain in the fixed porcine ear fibroblast cells......................................................................................................59 Figure 2-5. The methylaiton status detection in cloned porcine ear fibroblast cells by using 3xMBD protein......................................................................................................60 Figure 2-6. MBD immuonoprecipitate methylated DNA detected by pcr in cloned porcine genome of OPN gene.......................................................................................64 Figure 2-7. The detection of methylaiton status in lung cancer cells by using 3xMBD protein..................................................................................................................................65 Figure 3-1. The flow chart of the DMH. Agilent DHM chip with 12,000 spots was used for our analysis in cloned pig genome..........................................................73 Figure 3-2. The sample selection of DMH chip according to the methylation status of H19 putative DMR....................................................................................................86 Figure 3-3. The quality of DMH chip assays of cloned pig ear (CP12), heart (CP11), and testis (CP5)..............................................................................................................87 Figure 3-4. The distribution of CpG sites in the normal chromosome and analyzed tissues.................................................................................................................................88 Figure 3-5. The hierarchical clustering of analyzed genes among three chip data 89 Figure 3-6. The flowchart of the analysis method of DMH chip and its overlapped gene group showed in a pie diagram (for CP12 ear, CP11 heart, and CP5 testis) 91 Figure 3-7. The flowchart of the analysis method of DMH chip and its overlapped gene group showed in a pie diagram (for CP5 testis only).....................................92 Figure 3-8. The IPA analysis of the candidate genes..............................................94 Figure 3-9. The distribution of CpG sites, COBRA results, and bisulfite sequencing data in EXD3 gene......................................................................................................99 Figure 3-10. The distribution of CpG sites, COBRA results, and bisulfite sequencing data in PDZD4 gene......................................................................................................100 Figure 3-11. The distribution of CpG sites, COBRA results, and bisulfite sequencing data in MTMR7 gene......................................................................................................101 Figure 3-12. The distribution of CpG sites, COBRA results, and bisulfite sequencing data in IGF2R gene......................................................................................................102 Figure 3-13. The distribution of CpG sites, COBRA results, and bisulfite sequencing data in PEG3 gene......................................................................zh_TW
dc.language.isoen_USen_US
dc.publisher生命科學系所zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2208201211193400en_US
dc.subject去氧核醣核酸甲基化zh_TW
dc.subjectDNA methylationen_US
dc.subject上遺傳性修飾zh_TW
dc.subject銘印基因zh_TW
dc.subject核轉置技術zh_TW
dc.subject複製動物zh_TW
dc.subject再程式化作用zh_TW
dc.subject差異性甲基化區域zh_TW
dc.subject甲基化結合區zh_TW
dc.subject差異性甲基化雜合作用zh_TW
dc.subject染色體免疫共沉澱zh_TW
dc.subject衛星基因座zh_TW
dc.subjectEpigenetic modificationen_US
dc.subjectImprinted genesen_US
dc.subjectSomatic nuclear transfer techniqueen_US
dc.subjectCloned animalsen_US
dc.subjectReprogramming processen_US
dc.subjectDifferentially methylated regionsen_US
dc.subjectMethyl binding domainen_US
dc.subjectDifferentially methylated hybridizationen_US
dc.subjectChromatin immunoprecipitaionen_US
dc.subjectSatellite gene locusen_US
dc.title複製動物基因體中銘印及/或非銘印基因之甲基化樣貌剖析zh_TW
dc.titleDissecting methylation profiles of imprinted and/or non-imprinted genes in cloned animal genomesen_US
dc.typeThesis and Dissertationzh_TW
item.fulltextno fulltext-
item.languageiso639-1en_US-
item.openairetypeThesis and Dissertation-
item.cerifentitytypePublications-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextnone-
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