The interplay of TET1, DNA methylation and vitamin metabolism in neurulation.

Although folic acid (vitamin B9) intake is now recommended during early pregnancies to reduce incidences of neural tube defects (NTD), the most common birth defect worldwide, it is unclear why it is beneficial and whether there are risks with excessive intake. The effects of deficiency of another essential nutrient, vitamin C, during pregnancies are also unknown. As nutritional factors, both vitamins can influence the patterns of chemical marks called methylation which coat genetic information in DNA and can turn off messages encoded in genes. Here, we study a gene, TET1, that produces a protein that removes DNA methylation in the early embryo. We ask how absence of TET1 or vitamin C in mouse embryos affects DNA methylation, folate metabolism and development of early neuronal cells that form the brain. First, we will examine how loss of TET1 affects gene expression, opening of genomic regions and DNA methylation at an early stage of the mouse embryo that is morphologically similar to human. We will then examine whether lack of vitamin C or TET1 in mice, with excessive or deprived folate in their diet, will have long-lasting effects on DNA methylation and gene function of neuronal cells in the embryo by mid-gestation. Our studies will clarify the beneficial or unexpected adverse effects of vitamin nutrition in the presence of DNA methylation defects in the fetus during gestation, leading to better treatment or preventive measures for high-risk pregnancies.