luận văn identifying the effect of exposure to dioxin and furans on human health leading to diffuse large b lymphoma through gene network construction

THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY NGUYEN THI QUYNH LAM IDENTIFYING THE EFFECT OF EXPOSURE TO DIOXIN AND FURAN ON HUMAN HEALTH LEADING TO DIFFUSE LARGE B LYMPHOMA THROUGH GENE-NETWORK CONSTRUCTION BACHELOR THESIS Study Mode: Full-time Major: Environmental Science and Management Faculty: International Programs Office Batch: 2013 - 2017 Thai Nguyen, December 2017 n DOCUMENTATION PAGE WITH ABSTRACT Thai Nguyen University of Agriculture and Forestry Degree Program Bachelor of Environmental Science and Management Student name Nguyen Thi Quynh Lam Student ID DTN1353110372 Thesis Title Identifying the effect of exposure to dioxin and furans on human health leading to diffuse large B lymphoma through gene-network construction Supervisor(s) Prof ChunYu Chuang, Assoc Prof Tran Thi Thu Ha Abstract: Many studies indicated that exposure to dioxins and dioxins – compounds (e.g., 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated dibenzofurans (furans) can induce several outcomes on human and animal in the long term period, and one of them is diffuse large B lymphoma which is considered as the most popular kind of lymphoma In order to identify the gene expression altered by TCDD and Furans potentially underlying DLBCL development, bioinformatics meta-analysis was applied in this study In this study, 10 datasets containing the information of gene expression of DLBCL, TCDD and Furans were obtained from Gene Expression Omnibus (GEO) and Array Express websites, and further analyzed using Cytoscape software and its plugins – ClueGO and CluePedia As a result, the most differentially expressed genes were found to construct genenetworks of DLBCL, TCDD and furans and hence the potential pathway presented how dioxins could cause the progress of lymphoma In addition, the analytical result i n reported that TCDD and furans have a possibility to induce the receptor AhR which promotes the appearance of protein TWIST1 and enhance the progress of DLBCL The result of this study has made a great contribution for further dioxins study, and it is also considered as the initial steps of future work for DLBCL diagnosis and treatment Keywords: TCDD, Furans, DBLCL, bioinformatics, GEO, Array Express Number of pages: 87 Date of Submission: 20/09/2017 Supervisor’s signature ii n ACKNOWLEDGEMENT First of all, I would like to use this opportunity to express my deepest gratitude and special thanks to Prof Chun-Yu Chuang for her patient to guide and keep me on the correct path and show me many of wonderful things during the time of my internship at the Department of Biomedical Engineering and Environmental Science at National Tsing Hua University I would like to express my deep thanks to Assoc Prof Tran Thi Thu Ha for giving me necessary advices and guidance in order to complete my thesis My sincere thanks are also given to all the members working in the Department of Biomedical Engineering and Environmental Science for supporting me all the materials and necessities when conducting experiments for my research Finally, I would like to thank my family and my friends encouraging me and advising me during completion of this thesis Thai Nguyen, October 2017 Nguyen Thi Quynh Lam iii n TABLE OF CONTENTS ACKNOWLEDGEMENT iii TABLE OF CONTENTS iv LIST OF FIGURES vii LIST OF TABLES viii LIST OF ABBREVIATIONS ix PART I INTRODUCTION 1.1 Research rationale 1.2 Research objectives PART II LITERATURE REVIEW .3 2.1 Persistent Organic Compounds (POPs) 2.2 Dioxins and dioxin – liked compounds 2.3 Lymphoma and non – Hodgkin lymphoma 2.3.1 Diffuse large B lymphoma 2.3.2 SNPs of Diffuse Large B lymphoma 2.4 Gene - network components 10 2.4.1 Microarray data 10 2.4.2 Gene network database: Array Express and GEO 11 2.4.3 Statistical analysis 13 2.4.4 Hub – proteins 15 2.4.5 GO term 15 iv n luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction 2.5 Gene Network construction tools 16 2.5.1 Network Analyst website 16 2.5.2 Cytoscape software and plugins: ClueGO and CluePedia Apps 17 PART III METHODOLOGY 19 3.1 Data collection 19 3.2 Data processing 19 3.3 Network construction 21 PART IV RESULTS AND DISCUSSION 24 4.1 Results 24 4.1.1 Genetic datasets 24 4.1.2 Differentially genes expression 27 4.1.3 Gene-network construction of DLBCL, TCDD and Furans 33 4.1.4 Protein – protein interaction network of DLBCL, TCDD and Furans 35 4.1.5 Potential pathway showing the relation between TCDD and Furans and Diffuse Large B lymphoma 37 4.2 Discussion 39 4.2.1 AhR – mediated key factor of dioxins – like compounds 39 4.2.2 Key factors of hypoxia response and the risk of MYC – TP53 interaction 40 4.2.3 Inhibition of cancer cell apoptosis and tumorigenesis factor in DLBCL 42 PART V CONCLUSION 44 REFERENCES 46 luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction n v luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction APPENDICES 56 Appendix Differentially expressed genes of DLBCL versus normal cell 56 Appendix Differentially expressed genes of exposure to TCDD group and versus control group 63 Appendix Differentially expressed genes of exposure to FURANS group versus control group 67 Appendix Hub proteins of DLBCL network 74 Appendix Hub proteins of TCDD network 75 Appendix Hub proteins of FURANS network 76 luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction n vi luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction LIST OF FIGURES Figure 2.1: General molecular structure of polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (Source: Pereira, 2004) Figure 2.2: Representative structure of 2,3,7,8-tetrachhlorodibenzo-p-dioxins (TCDD) (Pereira, 2004) Figure 2.3: A schematic representation of signal transduction after TCDD/AHR interaction (Fracchiolla et al., 2016) 22 Figure 3.1: The flowchart of methodology Figure 4.1: Gene Ontology network showing the relationship of DLBCL, TCDD and Furans 32 Figure 4.2: Protein – protein interaction network constructed by CluePedia plugin in Cytoscape 36 Figure 4.3: Flowchart of proteins interaction and involved biological processes 37 luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction n vii luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction LIST OF TABLES 24 Table 4.1: Database of DLBCL 25 Table 4.2: Database of TCDD and Furans Table 4.3: Differentially expressed genes, including up-and down-regulated genes in Diffuse Large B lymphoma compared to normal cells 27 Table 4.4: Differentially expressed genes, including up-and down-regulated genes activated by TCDD compared to control group 29 Table 4.5: Differentially expressed genes, including up-and down-regulated genes activated by Furans compared to control group 30 Table 4.6: Lists of hub proteins containing in DLBCL, TCDD and Furans networks 34 luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction n viii luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction LIST OF ABBREVIATIONS ABC DLBCL activated B – cell like DLBCL AhR Aryl Hydrocarbon Receptor ARNT Aryl Hydrocarbon Receptor nuclear translocator B-NHL B cell non-Hodgkin lymphoma CRE CAMP response element DEG Differentially expressed genes DLBCL Diffuse large B cell lymphoma DNA Deoxyribonucleic acid DNMT1 DNA methyl transferase EGFR Epidermal growth factor receptor FDR False discovery rate GCB DLBCL Germinal center B-cell like DLBCL GEO Gene expression omnibus GO Gene ontology HAHs Halogenate aromatic hydrocarbon MAGE-ML Microarray and Gene Expression Markup Language MAGE-TAB Microarray Gene Expression - Tabular format MIAME Minimum information about microarray experiment MM Mismatch OC Organochlorine PCBs Polychlorinated biphenyls luan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.constructionluan.van.identifying.the.effect.of.exposure.to.dioxin.and.furans.on.human.health.leading.to.diffuse.large.b.lymphoma.through.gene.network.construction n ix