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研究生:許嘉心
研究生(外文):Chia-Hsin Hsu
論文名稱:以MethylCap-seq在犬淋巴瘤進行全基因組DNA甲基化分析
論文名稱(外文):Genome-wide DNA Methylation Analysis Using MethylCap-seq in Canine Lymphoma
指導教授:林辰栖李繼忠李繼忠引用關係
口試委員:廖泰慶蔡女滿邱亦涵
口試日期:2019-07-03
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:80
中文關鍵詞:犬高惡性度B細胞淋巴瘤DNA甲基化MethylCap次世代定序生物標記
DOI:10.6342/NTU201900709
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高惡性度B細胞淋巴瘤(high-grade B-cell lymphoma)在狗為最常見的淋巴瘤分型,且普遍認為可作為比擬人類疾病的動物模式。雖然高惡性度B細胞淋巴瘤對化療反應良好,但這個癌症仍無法被化療治癒,復發率高,抗藥性嚴重。DNA甲基化是被研究最透徹的表觀遺傳之一,且在癌症形成扮演重要角色。目前已熟知啟動子(promoter)的過度甲基化(hypermethylation)會造成某些抑癌基因的不活化。另一方面,除了在啟動子區域及重複的DNA序列會有甲基化的改變之外,過度甲基化的CpG島(CpG island)通常會調控可能抑制癌症的重要非編碼RNA(non-coding RNA)的表現。雖然目前很多研究使用微陣列(microarray)或次世代定序來揭示犬淋巴瘤的甲基化圖譜,但犬高惡性度B細胞淋巴瘤的統整機制及用於癌症診斷及預後監控的實用生物標記幾乎沒有被報導。在此研究中,為了要有效地且特別地針對犬高惡性度B細胞淋巴瘤描述其全基因組DNA甲基化模式的特徵,我們使用MethylCap及深度定序的方式來進行研究,此方法稱為MehthlCap-seq。以此方式,我們成功將犬的甲基化DNA片段抓下,並根據不同的CpG甲基化密度將甲基化DNA分為中高部分及低部分。我們分別在中高部分及低部分找到2,144及1,987個癌症特有的過度甲基化基因,且這些過度甲基化分布最多於內含子(intron)及啟動子區域。功能分析特別指出這些基因涉及與癌化相關的路徑,包括Hippo、PI3K-Akt 和Rap1訊息路徑。有趣的是,我們使用Protein-protein interaction(PPI)分析這些過度甲基化基因的交互作用時,發現最相關的訊息路徑與神經系統有關,例如「丙胺基丁酸神經元突觸(GABAergic synapse)」與「麩胺酸突觸(glutamatergic synapse)」,呼應近期研究發現神經生成在癌症建立中扮演關鍵角色。而在低部分中,「蛋白質消化與吸收」及「古柯鹼成癮」是在中高部分中沒有被發現的路徑,這兩個路徑已被指出可能與人類淋巴瘤有關。除此之外,我們使用MethylCap-seq發現14個基因在所有淋巴瘤樣本中過度甲基化,但在健康犬沒有甲基化。在此研究中所發現的KCNA3即在不同腫瘤中有被發現過度甲基化,這些癌症包括乳癌、肺癌、大腸結腸癌、腎臟癌、卵巢癌及前列腺癌。不僅如此,我們也找到在癌症中未曾被報導過的基因發生過度甲基化,例如ANKRD24。這些基因皆極有可能作為追蹤犬高惡性度B細胞淋巴瘤的生物標記。另外,犬高惡性度B細胞淋巴瘤的特殊甲基化圖譜也與臨床表現一致,表示異常的甲基化改變可能會影響腫瘤的表現。總結來說,此研究首度使用MethylCap-seq於犬高惡性度B細胞淋巴瘤來描述其全基因組DNA甲基化圖譜的特徵,且其結果指出過度甲基化的特定基因有潛力用來剖析癌化過程及挖掘生物標記以監控犬淋巴瘤的疾病進程。
Canine high-grade B-cell lymphoma (cHGBL) is the most common lymphoma subtype occurring in dogs accepted as a comparative model of the human disease. Despite being a chemo-responsive tumor, this disease remains incurable due to the high relapse rates and subsequent chemoresistance. DNA methylation is one of the most intensely studied epigenetic modifications and plays crucial roles in cancer development. It is well known hypermethylation in promoters can result in inactivation of certain tumor suppressor genes. On the other hand, apart from altering DNA methylation in promoter regions and repetitive DNA sequences, hypermethylated CpG islands usually associate with regulation of expression of noncoding RNAs that may be significant in tumor suppression. Though recently many studies have disclosed the methylation profiles of canine lymphoma using microarray or next generation sequencing, the integrative mechanisms of the cHGBL development and practical biomarkers for cancer diagnosis or prognostic monitor are hardly revealed. To efficiently and specifically characterize genome-wide DNA methylation pattern of cHGBL, MethylCap, a ChIP-based method, was used in the present study followed by deep sequencing, so called MethylCap-seq. With this strategy, we successfully captured canine methylated DNA fragments and obtained the MEDIUM-HIGH and LOW fraction of methylated DNA based on different CpG methylation density. We identified 2,144 and 1,987 cHGBL -specific hypermethylated genes in the MEDIUM-HIGH and LOW fraction, respectively, and these hypermethylated regions were enriched in the intron and promoter regions. Functional analysis highlighted pathways strongly related to oncogenesis, including Hippo, PI3K-Akt, and Rap1 signaling pathways. Interestingly, when analyzing the interaction of these hypermethylated genes using Protein-protein interaction (PPI) method, we found there were relevant signaling pathways associated with neuronal system, such as “GABAergic synapse” and “glutamatergic synapse”, echoing the recently novel findings that neurogenesis plays key roles in tumor establishment. In the LOW fraction, “protein digestion and absorption” and “cocaine addiction” were specifically identified, both of which have been suggested to be involved in human lymphoma. In addition, by using MethylCap-seq, 14 genes in the MEDIUM-HIGH fraction were revealed to be hypermethylated in all cHGBL cases but not in healthy dogs. KCNA3, a gene that has been reported being hypermethylated in various cancers including breast, lung, colorectal, kidney, ovarian, and prostate cancer, was also observed in cHGBL in the present study. Moreover, we also identified genes that have not been reported to play roles in cancer, such as ANKRD24. These genes might be highly potential signatures for tracing cHGBL. Also, the distinct methylation pattern of cHGBL showed a concordance with the clinical outcome, suggesting that aberrant epigenetic changes may influence the behavior of the tumor. Collectively, our study firstly characterized the genome-wide DNA methylation patterns using MethylCap-seq in cHGBL and the results propose that specific DNA hypermethylation holds promise for dissecting tumorigenesis and uncovering biomarkers for monitoring the progression of canine lymphoma.
口試委員會審定書 #
誌謝 i
中文摘要 ii
ABSTRACT iv
CONTENTS vi
LIST OF FIGURES ix
LIST OF TABLES x
ABBREVIATION TABLE xii
Chapter 1 Literature review 1
1.1 Canine high-grade B-cell lymphoma 1
1.2 The molecular basis of DNA methylation 2
1.3 DNA methylation abnormalities in cancer 3
1.3.1 DNA hypomethylation 4
1.3.2 DNA hypermethylation 4
1.4 DNA methylation markers in cancer 5
1.4.1 DNA biomarkers for clinical practice 5
1.4.2 Advantages of DNA hypermethylation as cancer biomarkers 6
1.4.3 DNA methylation markers for canine lymphoma 7
Chapter 2 Introduction 8
Chapter 3 Materials and methods 10
3.1 Cell lines 10
3.2 Clinical cHGBL samples and PBMC from healthy dogs 10
3.3 Genomic DNA extraction and quantification 11
3.4 Preparation of fragmented genomic DNA 11
3.5 MethylCap 11
3.6 Next generation sequencing 12
3.7 MethylCap-seq data analysis 13
3.8 Bisulfite conversion and methylation-specific PCR (MSP) 14
Chapter 4 Results 16
4.1 Genome-wide methylome analysis using MethylCap-seq uncovers novel methylated markers for canine lymphoma cell line CLBL-1. 16
4.1.1 Quantification of captured DNA 16
4.1.2 Identification of methylated candidates by MethylCap-seq 17
4.1.3 GO terms and KEGG pathways analysis 18
4.1.4 Verification of methylation related areas identified in MethylCap-seq 19
4.2 MethylCap-seq reveals potential tumorigenic mechanisms and candidate biomarkers of cHGBL. 19
4.2.1 Clinical characteristics of HGBL and healthy dogs 19
4.2.2 More differentially methylated regions in the MEDIUM-HIGH fraction were found in promoters and introns in cHGBL. 20
4.2.3 Aberrantly methylated genes in the MEDIUM-HIGH fraction are involved in key functions related to development, morphogenesis and oncogenesis in cHGBL. 21
4.2.4 Specific genes related to tumorigenesis of cHGBL in the MEDIUM-HIGH fraction. 23
4.2.5 More differentially methylated regions in the LOW fraction were found in promoters and introns in cHGBL. 24
4.2.6 Two enriched pathways were specifically identified in the LOW fraction. 25
4.2.7 Promoter hypermethylation of specific genes was less consistent in the LOW fraction of cHGBL. 25
Chapter 5 Discussion 27
5.1 Genome-wide methylome analysis using MethylCap-seq uncovers novel methylated markers for canine lymphoma cell line CLBL-1. 27
5.2 MethylCap-seq reveals potential tumorigenic mechanisms and candidate biomarkers of cHGBL. 30
Chapter 6 Conclusion 40
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