Jan Krzysztof Blusztajn

We study the effects of perinatal availability of an essential nutrient, choline, on brain development and aging in experimental animals. This research endeavors to determine why it is that supplementation with choline during critical perinatal periods in rats and mice causes a long-term facilitation of visuospatial memory which persists until old age. To this end we are utilizing biochemical, neuroanatomical, and behavioral techniques in a highly unified experimental design. Our studies to date have focused on the development of the basal forebrain cholinergic system, hippocampal MAPK and CREB signaling, and on the developmental patterns of brain gene expression ( Fig. 1). Recent data prompted us to test the hypothesis that the actions of choline are mediated by an epigenetic mechanism involving DNA methylation. Because choline is a donor of metabolic methyl groups its levels modulate the concentrations of cellular S?adenosylmethionine, a compound that serves as a substrate for DNA methylating enzymes. In turn, DNA methylation patterns modulate transcription of multiple genes. These methylation patterns are inherited through cell divisions, providing a possible epigenetic mechanism for modifications in brain gene expression observed many months after the dietary manipulation. Indeed, we found that prenatal availability of choline alters global DNA methylation and patterns of DNA methylation of key genes (e.g. insulin-like growth factor II, Igf2) whose expression is known to be regulated by this process. Our data are the first to indicate that choline nutrition in pregnancy alters the epigenome of the brain. Perhaps surprisingly, we observed upregulation of DNA methylation during choline deficiency. We hypothesized that this may be due to induced expression of DNA methylating enzymes by low choline supply. Indeed, choline deficiency increased the expression of DNA methyltransferases, DNMT1 and DNMT3A in brain and liver. These data point to an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. We are vigorously pursuing the testing of the methylation hypothesis [both as it relates to DNA and histones] and we are producing genetic mouse models that help us understand the mechanism of action of choline.