Functions of DNA Methylation Based on Studies in the 70’-80’, a Dogma Emerges Where DNA Methylation Is Associated with Transcriptional Repression
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Faculty of Pharmaceutical, Biomedical and Veterinary sciences Department of Biomedical sciences Protein chemistry, Proteomics and Epigenetic Signalling (PPES) Epigenetic profiling of adverse lifestyle conditions and nutraceutical interventions in health and disease Epigenetische profilering van ongunstige levensstijlfactoren en nutraceutische interventies bij gezondheid en ziekte Thesis submitted for the degree of doctor in science: biochemistry and biotechnology at the University of Antwerp to be defended by Ken Declerck Promotor: Prof. Dr. Wim Vanden Berghe Antwerp, 2019 Members of the jury Promotor: Prof. Dr. Wim Vanden Berghe Protein chemistry, Proteomics and Epigenetic Signalling (PPES), University of Antwerp, Belgium Chairman: Prof. Dr. Guy Van Camp Center of Medical Genetics, University of Antwerp, Belgium Internal members: Prof. Dr. Wim Martinet Physiopharmacology, University of Antwerp, Belgium Prof. Dr. Stuart Maudsley Translational Neurobiology, University of Antwerp, Belgium External members: Prof. Dr. Carmen Jerónimo Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), University of Porto, Portugal Prof. Dr. Claudia Santos Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Portugal iBET, Instituto de Biologia Experimental e Tecnológica, Portugal Table of contents List of abbreviations Summary Samenvatting Chapter 1: Introduction Chapter 2: Thesis outline and objectives Chapter 3: Prenatal pesticide exposure interacts with a common polymorphism in the PON1 gene leading to specific DNA methylation changes in genes associated with cardio-metabolic disease risk Chapter 4: Identification of CALD1 DNA Methylation as a saliva specific biomarker for early life psychosocial deprivation stress associated with institutional care Chapter 5: Identification of differentially methylated BRCA1 and CRISP2 DNA regions as blood surrogate markers for cardiovascular disease Chapter 6: Characterization of blood surrogate immune-methylation biomarkers for immune cell infiltration in chronic inflammaging disorders Chapter 7: Strong interindividual epigenetic variation in response to flavanol diet intervention reveals redundant gene wiring of cell adhesion networks Chapter 8: Standardized medicinal Echinacea purpurea tincture enforces monocyte innate immune response through priming of interferon and chemotaxis pathways Chapter 9: General discussion Acknowledgements Academic Curriculum Vitae 1 2 List of abbreviations 2-HG 2-hydroxyglutarate 3’MEC 3′-O-methyl(-)-epicatechin 4’MEC7G 4′-O-methyl(-)-epicatechin-7-β-D-glucuronide 5-AZA 5-azacytidine 5-Aza-CdR 5-aza-2′-deoxycytidine 5caC 5-carboxylcytosine 5fC 5-formylcytosine 5hmC 5-hydoxymethylcytosine 5mC 5-methylcytosine 5-MTHF 5-methyltetrahydrofolate 6mA N6-methadenine AD Alzheimer's disease AML acute myeloid leukemia aoSMC aortic smooth muscle cells AR androgen receptor AREase arylesterase athDMP atherosclerosis-DMP athDMR atherosclerosis-DMR Avy viable yellow allele AWHS Aragon Workers' Health Study AxinFu axin fused allele BEIP Bucharest Early Intervention Project BMIQ beta mixture quantile dilation CAUG care as usual group CB2 cannabinoid receptor 2 cfDNA cell-free DNA CGI CpG island chIP chromatin immunoprecipitation CML chronic myelomonocytic leukemia CRC colorectal cancer CRH corticotropin-releasing hormone cRNA complementary RNA CRP C-reactive protein CTCL cutaneous T cell lymphoma CTQ childhood trauma questionnaire 3 CUP carcinoma of unknown primary CVD cardiovascular disease DEX dexamethasone DMP differentially methylated position DMR differentially methylated region DNMT DNA methyltransferase DNMTi DNMT inhibitor DOHaD Developmental Origins of Health and Disease EC4’S (-)-epicatechin-4′-sulfate EGCG (-)-epigallocatechin-3-gallate eQTL expression quantitative trait locus ERV endogenous retrovirus ET1 endothelin-1 EWAS epigenome-wide association study FACS fluorescence-activated cell sorting FCG foster care group FDR false discovery rate FH fumarate dehydrogenase FMD flow-mediated vasodilation gDMR germline DMR gDNA genomic DNA GEO gene expression omnibus GR glucocorticoid receptor GRE glucocorticoid response elements GWAS genome-wide association study HDACi HDAC inhibitor HOMA-IR Homeostatic Model Assessment for Insulin Resistance HP1 heterochromatin protein 1 HUVEC human umbilical vein endothelial cells IAP intracisternal A-particle IC imprinted center ICR imprinted control region IDH isocitrate dehydrogenase IFN interferon IHEC International Human Epigenome Consortium IPA ingenuity pathway analysis LAD lamina-associated domain LDTF lineage-determining transcription factors 4 LOCK large, organized chromatin lysine modifications MAD median absolute deviation MBD methyl-binding domain mdNLR methylation-derived neutrophil/lymphocyte ratio MDS myelodysplastic syndrome meQTL methylation quantitative trait loci MOF monomeric and oligomeric flavanols MS multiple sclerosis MTHFR methylenetetrahydrofolate reductase NHP non-human primate NIG never institutionalized group NLR neutrophil/lymphocyte ratio NPC neuronal precursor cells PAI-1 plasminogen activator inhibitor type-1 PCA principal component analysis PD Parkinson's disease PGC primordial germ cells PGR progesterone receptor piRNA PIWI-interacting RNA ProgFib ENCODE fibroblast PTCL peripheral T cell lymphoma PTK tyrosine kinase PTSD post-traumatic stress disorder RCT randomized controlled trial SAH S-adenosylhomocysteine SAM S-adenosyl methionine SCLC small-cell lung carcinoma SDH succinate dehydrogenase SNP single-nucleotide polymorphism STK serine/threonine kinase TAD topologically associated domains TCGA The Cancer Genome Atlas TET ten-eleven translocation proteins TF transcription factor TFBS transcription factor binding site TSST Trier Social Stress Test UPD uniparental disomy VMP variable methylated position 5 WGCNA weighted correlation network analysis WHO World Health Organization 6 Summary DNA methylation is an epigenetic mark which plays an important role in maintaining cellular identity by regulating cell and tissue-specific gene expression profiles. Epigenetic modifications are known to be influenced by both genetic and environmental factors and may therefore be seen as a bridge between the environment and the genome. Furthermore, epigenetic changes due to environmental stimuli may be mitotically inherited and thus also function as a cellular memory. Given these characteristics, DNA methylation is thought to mediate the long-term effects of chronic exposure to environmental factors on health and disease, which is also known as the Developmental Origins of Health and Disease (DOHaD) hypothesis. This paradigm proposes that the prenatal and early developmental stages are important contributors of an individual’s health status throughout its life. Indeed, DNA methylation changes are now also identified in multiple lifestyle diseases, such as cancer, cardiovascular, metabolic and neurological diseases. Due to its dynamic nature, DNA methylation can be exploited as prognostic, diagnostic and therapeutic biomarkers, but also is an attractive target for therapeutic and nutritional interventions. In addition, studying epigenetic patterns could give us useful mechanistic insight in disease etiology and development. In this thesis, we studied DNA methylation patterns in easy-accessible tissues, including blood and saliva to monitor adverse early environmental exposures, cardio-metabolic diseases and nutritional intervention responses. In the first part of the results section (chapters 3 and 4), we examine whether early adverse environmental conditions can be monitored through DNA methylation marks in blood and saliva. During prenatal and early development, the methylation profile is sensitive to adverse environmental factors and the exposure history builds up cellular memory which can promote diseases later in life. In this way, monitoring adverse DNA methylation changes holds promise to monitor and/or prevent potential disease risk later in life. In chapter 3, we performed a pilot study in a cohort of Danish children, whose mothers were exposed to pesticides during pregnancy. In a previous study of those children, it was found that carriers of a polymorphism in the PON1 enzyme, which has an important role in organophosphate pesticide hydrolysis and is linked with atherosclerosis, have an adverse cardio-metabolic risk profile upon pesticide exposure. We could detect a specific DNA methylation profile in blood of prenatally pesticide exposed children carrying the PON1 192R-allele. Differentially methylated genes were enriched in several neuroendocrine signaling pathways including dopamine-DARPP32 7 feedback (appetite, reward pathways), corticotrophin releasing hormone signalling, nNOS, neuregulin signalling, mTOR signalling and type II diabetes mellitus signalling suggesting a possible link with the metabolic effects observed in these children. Furthermore, we were able to identify possible candidate genes which mediated the associations between pesticide exposure and increased leptin level, body fat percentage, and difference in BMI Z-score between birth and school age. In chapter 4, we compared DNA methylation profiles in saliva samples of neglected orphan children of the well characterized Bucharest Early Intervention Project (BEIP), raised in institutions, following foster care or never-institutionalized children. We identified a set of 30 differentially methylated regions (DMRs) located in genes which are involved in nervous system and neuronal development, related to cognition,