There is accumulating evidence that the pathogenesis of many adult-onset chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer, can be influenced by nutrition in early life. One probable underlying mechanism is through early nutritional effects on epigenetics, i.e. self-perpetuating gene regulatory systems that are not dependent on DNA sequence. A particularly relevant epigenetic mechanism involves the methylation of cytosine residues on both strands of palindromic CpG dinucleotides. Mammalian one-carbon metabolism, which provides the methyl groups for biological methylation reactions, is highly dependent on dietary substrates and cofactors. Thus, the establishment and maintenance of genomic methylation patterns during early development may make it more critical to maintain appropriate levels of these diet-derived components at that time than during later life. The overall hypothesis of the proposed research is that maternal dietary methyl donor supplementation before conception and during pregnancy alters DNA methylation of specific genomic regions in the early embryo, and that these induced epigenetic alterations persist to adulthood. We propose to test this hypothesis in mouse models, focusing on two gene classes: genes adjacent to transposon elements, and genomically imprinted genes. Understanding the specific biologic mechanisms linking early nutrition to adult gene expression and metabolism may ultimately enable early-life nutritional interventions aimed at ameliorating adult-onset chronic disease in humans. This proposal describes a five-year training program for the development of an academic career in Nutrition and Developmental Genetics. The proposed research builds upon previous work by the principal investigator, and entails developing new approaches that will broaden his research capabilities. The applicant's long-term goals include building on this animal model research to develop specific hypotheses regarding early nutritional influences on epigenetic gene regulation in humans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Baylor College of Medicine
Schools of Medicine
United States
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Waterland, Robert A; Kellermayer, Richard; Rached, Marie-Therese et al. (2009) Epigenomic profiling indicates a role for DNA methylation in early postnatal liver development. Hum Mol Genet 18:3026-38
Waterland, Robert A (2009) Is epigenetics an important link between early life events and adult disease? Horm Res 71 Suppl 1:13-6
Waterland, Robert A (2009) Early environmental effects on epigenetic regulation in humans. Epigenetics 4:523-5
Waterland, R A; Travisano, M; Tahiliani, K G et al. (2008) Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond) 32:1373-9
Waterland, Robert A (2008) Epigenetic epidemiology of obesity: application of epigenomic technology. Nutr Rev 66 Suppl 1:S21-3
Shen, Lanlan; Waterland, Robert A (2007) Methods of DNA methylation analysis. Curr Opin Clin Nutr Metab Care 10:576-81
Waterland, Robert A; Travisano, Michael; Tahiliani, Kajal G (2007) Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J 21:3380-5
Waterland, Robert A; Michels, Karin B (2007) Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 27:363-88
Waterland, Robert A; Lin, Juan-Ru; Smith, Charlotte A et al. (2006) Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15:705-16
Waterland, Robert A; Dolinoy, Dana C; Lin, Juan-Ru et al. (2006) Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44:401-6