Evidence from human epidemiologic and animal mode] studies suggests that the pathogenesis of many adult-onset chronic diseases, including type 2 diabetes, cardiovascular disease, and obesity and cancer is influenced by nutrition in early life. Early nutritional effects on epigenetic gene regulation constitute a probable underlying mechanism. The overall hypothesis of the proposed research is that there are specific classes of mammalian genes whose epigenetic states are labile to nutritional influences during early development. We propose to test this hypothesis in mouse models, focusing on two gene classes known to be epigenetically regulated: genes adjacent to transposon elements, and genomically imprinted genes.
The specific aims of the proposed research are to: 1) test the hypothesis that the epigenetic metastability associated with specific transposable element insertions causes the epigenetic state of neighboring genomic regions to be labile to early nutritional influences, and 2) test the hypothesis that post-weaning diet influences allelic expression of imprinted Igf2 by altering CpG methylation within the Igf2/H19 imprinting control region. Understanding the specific biologic mechanisms linking early nutrition to adult gene expression and metabolism may ultimately enable early-life nutritional interventions to alleviate chronic disease in humans.
| 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 (2006) Epigenetic mechanisms and gastrointestinal development. J Pediatr 149:S137-42 |
| Waterland, Robert A (2006) Assessing the effects of high methionine intake on DNA methylation. J Nutr 136:1706S-1710S |
| Waterland, Robert A (2005) Does nutrition during infancy and early childhood contribute to later obesity via metabolic imprinting of epigenetic gene regulatory mechanisms? Nestle Nutr Workshop Ser Pediatr Program 56:157-71; discussion 171-4 |
