Epigenetic events in micronutrient programming during early development

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Although the information content of the DNA is determined primarily by its nucleotide sequence, further modifications of the DNA itself or the proteins binding to it are important to determine which genes are turned on and off. These modifications are influenced by environmental factors. One of them, methylation of the DNA molecule is dependent on the supply and metabolism of several vitamins and trace elements, such as folic acid, vitamins B6 and B12 and zinc. If pregnant mice are given food deficient in these factors, DNA methylation in the offspring is altered with resultant changes in gene regulation. A similar mechanism is possible in humans and could account for permanent consequences of micronutrient (that is, vitamin and trace element) deficiencies, however, data supporting this hyposthesis are lacking. Our aim is to study whether the micronutrient supply of the pregnant mother during early human embryonic development influences DNA methylation in the offspring. Of particular interest is the DNA methylation of genes which could potentially effect growth and development of the embryo and placenta. We will take advantage of an ongoing trial run by the MRC Keneba Field Station in the Gambia. This is a double blind, randomised control trial food supplementation containing multiple micronutrients given to women of childbearing age living in rural Gambia. The major endpoints of the study are fetal growth, placental development, weight, length and head circumference of the newborn infant. We will study DNA from children whose mothers received micronutrient supplementation and from those whose mothers received placebo only. Using this design we will study whether micronutrients supplementation has an effect on total methylation of the genome using a simple biochemical assay. We will also use methods that assess methylation at large numbers of specific points throughout the human DNA at the sametime in order to identify genes which are methylated in one group of subjects but not in the other group. The latter method includes the use of microarray (DNA chip) technology that allows for genome-wide methylation analysis in one experiment. We will also investigate DNA methylation of individual 'imprinted' genes. These are particularly interesting candidates for epigenetic modulation as any one of the two copies, either the maternal or the paternal switched on and this is mainly regulated by DNA methylation of sequences called 'imprinting centres'. We will investigate and compare DNA methylation of 9 imprinting centres controlling 8 groups of such imprinted genes. Many of these genes are thought to be important in the control of growth of the unborn child. We will, therefore, assess whether DNA methylation of these 'imprinting centres' is different in individuals with or without maternal micronutrient supplementation. If the trial shows that micronutrient supplementation does indeed improve the growth of the fetus, the weight of the placenta, the size of the newborn then our data could provide supportive evidence that this may be related to altered methylation of these imprinted genes. Evidence in humans that periconceptual variation in nutrients can result in permanent epigenetic changes would have profound effects on the direction of future human developmental biology. It would initiate follow up studies to investigate the consequence of such changes in terms of gene function and could open up new avenues for drug development. For health care professionals and the general public, it would lead to more detailed examination of the importance of maternal diet both before and during pregancy.