In this thesis we aimed to get insight in how the methylome is established during development and subsequently degenerates during ageing using an integrative approach to the analysis of DNA... Show moreIn this thesis we aimed to get insight in how the methylome is established during development and subsequently degenerates during ageing using an integrative approach to the analysis of DNA methylation in conjunction with other levels of genomics data. The first two empirical chapters of this thesis describe the establishment and the maintenance of the epigenome during fetal development and in later life in multiple tissues. In the subsequent two chapters we investigated the loss of control over the methylome in blood and other tissues. Show less
This thesis is a study on the link between early development and adult health. Studies in animal models indicate that so-called epigenetic marks may be influenced by nutrition during development,... Show moreThis thesis is a study on the link between early development and adult health. Studies in animal models indicate that so-called epigenetic marks may be influenced by nutrition during development, changing the expression of genes implicated in disease. Epigenetics may therefore link development and disease. To investigate this hypothesis in humans we studied DNA methylation, a key epigenetic mark, in individuals exposed during early gestation to the Dutch Famine and individuals born growth restricted, which is also alleged to relate to malnutrition. DNA methylation at metabolic and developmental genes was associated with early gestational famine exposure to the Dutch Famine and the patterns of the associations mirrored the epidemiological findings. The associations found with prenatal famine exposure did not relate to prenatal growth restriction, adding evidence that prenatal growth restriction is not linked with m alnutrition in Western cohorts. Further characterization showed that DNA methylation differences associated with prenatal famine exposure are independent of genetic variation, cluster along biological pathways and within regulatory regions and may relate to the phenotypic consequences of prenatal malnutrition. The work described in this thesis gives credence to the hypothesis that epigenetic marks may be the molecular link between development and later disease in humans Show less
