Modifications of DNA and chromatin impact the accessibility of the genetic code to the biological machinery of the cell. Relating epigenomic changes to neurodevelopmental disorders has been challenging. One obstacle is the need to study the relevant tissues at an appropriate stage of the disease process, while another is the difficulty of understanding the relationship of nucleotide and chromatin modifications to complex genetic disorders in which multiple loci interactions underlie expression of the disease. We propose to take advantage of a disorder, neural tube defects (NTDs), in which the existing mouse models closely parallel the human disease and in which several lines of evidence indicate a strong influence in both mouse and man of epigenetic modifications regulating disease expression. We will combine proof of principle studies in the mouse with investigations of human NTD cohorts to examine the relationship between DNA/chromatin methylation and the expressivity of NTDs in genetically susceptible individuals. The study of epigenetic events contributing to NTDs has multiple distinct advantages over epigenomic investigation of other human diseases, as more than 200 genes are implicated in NTDs by human or animal studies. These provide critical clues to molecular pathways important for normal neurulation. Supporting the existing clinical data, we discovered several NTD-prone mouse mutant lines in which NTD occurrence is sensitive to folic acid supplementation. Folate metabolism is the source of al S-adenosyl methoinine (SAM), which is the primary methyl donor for methylating nucleic acids, proteins and lipids. Providing methyl donors is thought to be a major route through which folate supplementation exerts its beneficial effects on neurulation. We will use cutting edge and emerging technologies applied to mouse and human patient material to interrogate genome wide methylation and chromatin remodeling interactions, correlated with individual genotype, to examine epigenetic effects on the transcriptome and on phenotypic outcome. This proposal tests the hypothesis that epigenetic modifications in DNA and chromatin in the setting of prenatal supplementation that modulates DNA and chromatin methylation will impact a recognizable pattern of gene expression to either favor or impair neurulation in a manner that can be predicted based on individual genotype. Moreover, we hypothesize that certain patterns will be evident not only in the developing neural tube but also in the peripheral blood and so will be useful in evaluating risk and optimal NTD prevention in a clinical setting. We predict that some DNA and chromatin methylation signatures acquired in utero wil persist postnatally, regardless of whether supplementation continues after birth. Finally, we expect that DNA methylation patterns found in mouse will be present as well-at least at the level of pathways if not individual genes-in human patients affected by an NTD.
There is a critical need to identify patterns of human genetic--modified by epigenetic--variation that will allow individual risks to be accurately assessed. This would enable NTD prevention strategies to be optimized for each family, rather than basing recommendations on whole populations. With our food supply now fortified, folic acid has become the most widely administered medicinal agent in the US today. Therefore, this study will also have broad relevance to human disorders in which folate intake has an implicated role, including major depression, autism, Alzheimer's disease, among others.
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