臺灣博碩士論文加值系統

小胖威力症 (Prader-Willi Syndrome, PWS) 是一種神經發育失調的疾病，它是由於來自父系的功能基因 15q11-q13 產生缺失及母系基因先天甲基化而關閉所造成的。此母系基因先天甲基化稱為基因烙印來產生基因缺失，加上源自於父系的基因表現發生缺陷造成兩套基因均不作用而致病。本次研究旨在提供小胖威力症患者其全基因體之甲基化情形。我們發展一個新穎的方法為 PCR Selective Suppression Hybridization (PSSH)，用於掃瞄小胖威力症患者與非患病者之間有不同甲基化情形的基因群。此種方法是在經過 subsequent bisulfite 實驗、USER 酵素切段、使用 biotin dCTP 標定及使用 streptavidin 分開被甲基化且未被 biotin 標定之 DNA 及未被甲基化且被 biotin 標定的 DNA 之後，再將已甲基化且未被 biotin 標定之 DNA 分別與來自小胖威力症患者及其母親之未甲基化且已被 biotin 標定的 DNA 雜合。目前，已有兩組小胖威力症患者的家庭經 Database for Annotation, Visualization and Integrated Discovery (DAVID) 以及 Pathway Interaction Database (PID) 等資料庫進行廣泛的分析，並從部份基因及基因組中已經辨識出 CREBBP， RRM1，HPP1 及 XRCC6 等與小胖威力症有所關聯之基因。而由先前其他已出版的論文中可以得知，這些候選基因在 DNA 甲基化以及 histone 修飾時，具有調控的功能。在與 NCBI 資料庫中已確認之小胖威力症相關基因進行比較後，發現這些候選基因也是 androgen receptor activity 及 E2F transcription factor network pathway 的一部份。為了証明此項假設，未來會使用 real-time PCR (qPCR)，methylation specific PCR (MSP) 以及 bisulfite sequencing PCR (BSP) 等方法再進行確認。

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of functional paternal copy of 15q11-q13. Epigenetic aberrations due to genomic imprinting defect leads to the absence expression of paternally-inherited genes. This study aims to provide an overview of the methylation status of the whole-genome among PWS patients. A novel method PCR Selective Suppression Hybridization (PSSH) was employed to screen the putative genes that are differentially methylated among PWS patients but not in normal individuals. This method utilizes hybridization of methylated-non-biotin labeled DNA and unmethylated-biotin-labeled DNA from the PWS patient and mother, respectively, after subsequent bisulfite treatment, USER enzyme cleavage, labeling with biotin dCTP and separation by streptavidin. After successful screening of two families, several genes and gene clusters were identified that could possibly link to PWS after comprehensive analyses using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Pathway Interaction Database (PID): CREBBP, RRM1, HPP1 and XRCC6. Based on the previous published results, these candidate genes were found to have cross-talk mechanisms that link between DNA methylation and histone covalent modifications. From the confirmed PWS-related genes based on OMIM (NCBI), co-regulation of androgen receptor activity and E2F transcription factor network pathways could be candidate related pathways on the screened putative genes. In order to establish these hypothetical results, more PWS samples are needed for the analysis; and will be confirmed using real-time PCR (qPCR), methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP).

CONTENTS

中文摘要 I
ABSTRACT III
ACKNOWLEDGEMENT V
CONTENTS VII
LIST OF FIGURES XI
LIST OF TABLES XIII
INTRODUCTION 1
1.1 Epigenetics 2
1.1.1 Histone Covalent Modification 2
1.1.2 DNA Methylation 3
1.2 Genomic Imprinting and DNA Methylation. 7
1.2.1 Characteristics of Imprinted Genes. 11
1.2.2 Molecular Bases of Imprinting Regulation. 13
1.2.3 Disorders of Genomic Imprinting. 17
1.2.3.1 Beckwith-Wiedemann Syndrome. 18
1.2.3.2 Silver- Russell Syndrome. 19
1.2.3.3 Prader-Willi Syndrome. 20
1.2.3.3.1 Clinical Features. 21
1.2.3.3.2 Molecular Classes of PWS. 22
1.2.3.3.3 Genetic Basis of PWS. 23
1.2.3.3.4 The Structure of PWS region. 24
1.2.3.3.5 Imprinted genes within 15q11-q13 related to PWS. 25
1.2.3.3.6 Mechanisms of Imprinting in PWS. 27
1.3 Aims of the Study 32
MATERIALS and METHODS 33
2.1 Research Strategy 34
2.2 PWS and Maternal Genomic DNA 35
2.3 Bisulfite treatment (Qiagen® Epitech Bisulfite) 35
2.4 USERTM Enzyme NEB® treatment 36
2.4.1 Materials 36
2.4.2 USERTM Enzyme NEB® reaction 37
2.5 Biotin-14-dCTP (Invitrogen TM) Labeling 38
2.5.1 Materials 38
2.5.2 DNA polymerase I (E.coli) NEB® reaction 38
2.6 Ligation of Nicks by T4 DNA Ligase (TAKARA) 39
2.7 Separation of biotin-labeled DNA by Dynabeads® Streptavidin (InvitrogenTM) 39
2.8 Mung Bean Nuclease NEB® treatment 41
2.8.1 Mung Bean Nuclease NEB® reaction 41
2.9 Adapter ligation 42
2.9.1 Materials 42
2.9.2 Adapters 42
2.9.3 Double stranded adapter working solution 43
2.9.4 Adapter Ligation 43
2.10 PCR Selective Suppression Hybridization (PSSH) 43
2.10.1 Materials 43
2.10.2 Suppression Hybridization 44
2.10.3 Primary PCR selection 44
2.10.4 Secondary PCR selection 45
2.11 TA cloning 45
2.11.1 Preparation of Electrocompetent Cells 46
2.11.2 TA Cloning 47
2.11.3 Electroporation 47
2.11.3.1 Materials 47
2.11.3.2 Transformation of E. coli by Electroporation (BIO-RAD® MicroPulser) 49
2. 12 Clone Insert Analysis by PCR 49
2.13 Electrophoresis 50
2.13.1 Materials 50
2.14 Sequencing and Bioinformatics Analysis 51
RESULTS 52
DISCUSSION 65
4.1 Principle of PCR Selective Suppression Hybridization (PSSH) 66
4.2 Candidate Genes 67
4.3 OMIM Confirmed PWS’s Potential Epigenetic Results 70
4.4 Drawbacks of PSSH Method 70
REFERENCES 72
APPENDIX 82


LIST OF FIGURES

Figure 1.1. Post-translational histone modifications. 3
Figure 1.2. CpG methylation. 4
Figure 1.3. DNA methylation, CpG islands and genome defense. 6
Figure 1.4. The two major phases of genome-wide erasure of DNA methylation in the early embryo and in primordial germ cells (PGCs). 9
Figure 1.5. Erasure, establishment, and maintenance of methylation imprints. 14
Figure 1.6. Key stages of genomic imprinting during development. 15
Figure1. 7. Molecular defects in PWS and AS. 21
Figure 1.8. Summary of the genetic and expression map of chromosomal region 15q11.2 – q13. 25
Figure 2.1. Research Strategy 34
Figure 2.2. PCR Selective Suppression Hybridization (PSSH) 35
Figure 3.1. Primary PCR after PCR Selective Suppression Hybridization (PSSH) 54
Figure 3.2 Secondary PCR after PCR Selective Suppression Hybridization (PSSH) 55
Figure 3.3. Insert Analysis by PCR after TA cloning 55
Figure 3.4. Common Candidate Genes from Analyzed PWS patients 58
Figure 3.5. Co-regulation of Androgen Receptor Activity. 60
Figure 3.6. E2F Transcription Factor Network. 61

LIST OF TABLES

Table 3.1 PWS patients and their respective parents. All PWS samples have deleted IC center in Chromosome 15. 53
Table 3.2 Common Candidate Genes from Analyzed PWS patients 56
Table 3.3 Relationship of PWS-Related Genes with Candidate Genes by DAVID and PID Analysis 59
Table 3.4 Brief Description of Genes related to PWS and the Candidate Genes by DAVID and PIDAnalysis 83
Table 4.1 Gene Cluster 1: Cell matrix interaction which includes cell adhesion function, peptidase activity, transmembrane proteins and cytoskeleton. 90
Table 4.2 Gene Cluster 2. Eye-Disease related genes 97
Table 4.3 Gene Cluster 3. Lymphocyte Development 98
Table 4.4 Gene Cluster 4. Cell Cycle and Apoptosis 100
Table 4.5 Gene Cluster 5. Metabolic Processes 102
Table 4.6 Gene Cluster 6. Bone, Muscle and Embryo Development 105
Table 4.7 Gene Cluster 7. Nuclear Function such as gene regulation 107
Table 4.8 Gene Cluster 8. Neuron Development 112

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