Epigenetische profilering van ongunstige levensstijlfactoren en nutraceutische interventies bij gezondheid en ziekte
13 november 2019
UAntwerpen, Campus Drie Eiken, Gebouw O, Auditoriuim O5 - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Wim Vanden Berghe
Doctoraatsverdediging Ken Declerck - Departement Biomedische Wetenschappen
DNA methylation is an epigenetic mark which plays an important role in maintaining cellular identity by regulating cell and tissue-specific gene expression profiles. Environmental and lifestyle factors influence DNA methylation resulting in long-term effects on health or diseases, such as cancer, cardiovascular diseases, metabolic and neurological disorders. Therefore, DNA methylation changes can be exploited as prognostic, diagnostic and therapeutic biomarkers. In addition, studying epigenetic patterns could give us useful mechanistic insight in disease etiology and development, or reversibility can be evaluated in therapeutic and nutritional interventions. In this thesis, we studied DNA methylation patterns in easy-accessible fluids, including blood and saliva to monitor adverse early environmental exposures, cardio-metabolic diseases and nutritional intervention responses.
We characterized DNA methylation profiles in blood and saliva samples associated with early adverse conditions, exemplified by children prenatally exposed to pesticides or orphan children grown up in institutions, suffering from chronic stress. In addition, methylation changes were localized in functionally relevant genes which may underly the different health outcomes.
In the second part of the thesis, an atherosclerosis-associated methylation profile in blood samples was determined. Differentially methylated regions were identified in BRCA1 and CRISP2 genes in both, blood samples as well as aortic atherosclerotic plaque tissues. These DMRs were further associated with subclinical atherosclerosis measures, supporting their usefulness as early diagnostic markers. In addition, a similar DNA methylation profile could be observed in blood and brain tissues of Alzheimer’s disease patients. Interestingly, the latter signature is driven by changes in blood immune cell type composition and immune cell infiltration.
In the final part of the thesis, we demonstrated widespread epigenetic effects of cardio-protective flavanols in vitro. Interestingly, despite substantial inter-individual epigenetic variation in response to a flavanol diet intervention, individual changes may affect common cell adhesion pathways. Furthermore, we identified reciprocal atherosclerosis and flavanol diet specific epigenetic changes, which involve systemic immunological changes in blood cell types.
In the final chapter of the thesis, an immunomodulatory echinacea extract was found to activate the interferon kinase signaling pathway involving changes in endogenous retroviral gene expression and DNA methylation profiles.
In conclusion, this work demonstrates the applicability of DNA methylation signatures of blood and saliva as health or disease biomarker, but also points to limitations and challenges which must be overcome in future studies to fully exploit the potential of epigenetics in personalized health applications.