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Genomics and Epigenomics of Common Human Metabolic and Heart Disease

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Genomics and Epigenomics of Common Human Metabolic and Heart Disease GENOMICS AND EPIGENOMICS OF COMMON HUMAN METABOLIC AND HEART DISEASE by Michael Lewis Multhaup A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland February, 2015 Abstract The field of epigenetics is rapidly becoming recognized as playing an essential part in explaining common human disease. Here we probe DNA methylation in diabetes mellitus and associated metabolic phenotypes and coronary heart disease. In a cohort from the Framingham Heart Study, we use epidemiological techniques to identify over 20,000 CpGs differentially methylated in coronary heart disease patients. In the other chapters, we use a functional approach to investigate the epigenetics of Type 2 Diabetes (T2D) and combine three lines of evidence – diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and evidence of T2D clinical risk – to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass surgery, identifying regions where both the location and direction of methylation change is conserved. These regions overlap with 27 genomic locations with genetic T2D risk, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed five genes with novel roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk. Advisor: Andrew P. Feinberg Reader: William G. Wong ii Table of Contents Acknowledgments…………………………………………………………………………………………………….………..…….4 List of Figures…………………………………………………………………………………………………………….……….….…6 List of Tables……………………………………………………………………………………………………………….….…….….7 Chapter 1: The history and current status of epigenetics……………………………………….……..………….8 Chapter 2: The epigenetics of obesity and insulin resistance…………………………………………….…….27 Chapter 3: Interaction between genomics and epigenomics of Type 2 Diabetes…………….……….41 Chapter 4: Epigenetic changes in Coronary Heart Disease in the general population………….…..74 Figures…………………………………………………………………………………………………………………………………….91 Tables……………………………………………………………………………………………………………………………………..143 Curriculum Vitae………………………………………………………………………………………………………………..……146 Appendix: Supplementary tables for genome-wide results……………………………….See Attached File iii Acknowledgements There have been many, many people who have had an impact on my graduate student career. Fellow students, friends, faculty, and family have all contributed to shape my journey through the Hopkins BCMB program. I would specifically like to thank my PI and mentor, Andy Feinberg. He has contributed to my growth both as a scientist and a mature adult. From him, I have not just learned about epigenetics, but also scholarship, thoughtfulness, critical thinking and professionalism. I could not have done this PhD without all the other members of the Feinberg Lab as well, who have contributed scientific insight and aid too numerous to mention. The members of the Epigenetic Center core facility have made this project possible, as we would have no array data without their expertise. My thesis committee has also been invaluable during this process, and I would like to thank William Wong, Natasha Zachara and Andrew Jaffe for their patience and scientific advice. This work was supported by NIH Director Pioneer Award DP1 ES022579 to Andrew Feinberg, by NIDDK R01 grant DK084171 to William Wong, by the Novo-Nordisk Foundation and Stockholm County Council to Erik Naslund and Juleen Zierath, and by the European Research Council to Juleen Zierath. We thank Arni Runarsson for technical assistance. Michael Multhaup performed all of the molecular biology experiments and the Infinium 450k regression modeling, as well as performing many of the other statistical analyses in conjunction with Andrew Jaffe. Marcus Seldin performed the dietary manipulations of mice and isolated tissues under the oversight of Guang William Wong, with the help of Mehboob Hussain and his lab. Shelley Lei performed the functional studies of glucose uptake under the oversight of Guang William Wong. Andrew Jaffe performed statistical analysis. Alexander Drong and Mark McCarthy performed MAGENTA analysis. Henriette Kirschner, Erik Naslund and Juleen Zierath provided samples from the human obesity and RYGB cohort. Andrew Feinberg was responsible for the iv design and oversight of all of the experiments and wrote papers with Michael Multhaup and considerable insight and assistance from Andrew Jaffe, Mark McCarthy, and Juleen Zierath. v List of Figures Figure 1: Diagrammatic explanation of our experimental design and results ......................................... 63 Figure 2: Genome-wide significant methylation changes related to diet-induced obesity in C57BL/6 mice............................................................................................................................................................. 64 Figure 3: Correlation of metabolic traits in diet-induced obesity mouse model ..................................... 66 Figure 4: Replication of mouse methylation changes in additional mice, and associated gene expression changes .................................................................................................................................... 67 Figure 5: Correlation of methylation and gene expression in mouse and human adipose tissue .......... 69 Figure 6: Significance of methylation change overlap between mouse and human tissues ................... 71 Figure 7: Consistent mouse-human methylation changes ........................................................................ 72 Figure 8: Overlapping methylation changes in human and mouse adipose tissue .................................. 73 Figure 9: Diagrammatic representation of the interactions between epigenetically conserved and genetically-associated genes implicated in this study .............................................................................. 74 Figure 10: Enrichment of connections between genes implicated by methylation and genome-wide significant GWAS genes .............................................................................................................................. 76 Figure 11: Overexpression and shRNA-mediated knock down of selected genes in 3T3-L1 adipocytes 77 vi List of Tables Table 1: Genome-wide significant mouse DMRs ....................................................................................... 79 Table 2: Mouse comprehensive high-throughput array-based relative methylation (CHARM) results (results in attached Appendix 1) ................................................................................................................ 81 Table 3: Adipocyte DMRs with genes in common between adipocyte and pancreatic islet analyses .... 82 Table 4: Gene ontology for genes near DMRs ........................................................................................... 83 Table 5: Mouse pyrosequencing replication results ................................................................................. 84 Table 6: Results of qPCR assay to test adipose tissue purification ........................................................... 90 Table 7: Conserved mouse/human adipose tissue DMRs ......................................................................... 91 Table 8: Enrichment of cross-species DMRs over DIAGRAM GWAS loci ................................................ 103 Table 9: Conserved mouse-human DMRs with genetic T2D risk loci association .................................. 104 Table 10: Cross-species, directionally consistent pancreatic islet DMRs that overlap with DIAGRAM T2D GWAS loci .......................................................................................................................................... 108 Table 11: Overlap of conserved and directionally consistent adipose DMRs and adipose enhancers . 110 Table 12: Human Subject Information ..................................................................................................... 115 Table 13: Pyrosequencing Primers ........................................................................................................... 118 Table 14: Quantitative PCR primers ......................................................................................................... 122 Table 15: Univariate statistics for Framingham Heart Study coronary heart disease cohort ............... 123 Table 16: Bivariate statistics for Framingham Heart Study coronary heart disease cohort .................. 124 Table 17: Top results for Framingham Heart Study coronary heart disease EWAS ............................... 125 vii Chapter 1 The history and current status of epigenetics Epigenetics is typically defined as maintenance or reproduction of information through cellular division that occurs without changes in the primary DNA sequence. Originally coined by Conrad Waddington in 1942, the term “epigenetics” was originally used to mean the forces that shaped genotype into phenotype according to his “canalization” theory where the almost infinite potential chaos of the human genome was channeled into a much smaller number of recognizable phenotypes (Waddington, 1942). Many years later, Robin Holliday, contemplating his studies
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