The article by Waterland and Jirtle explores the hypothesis that early nutritional influences on DNA methylation can affect adult metabolism and disease susceptibility in humans and other mammals. They focus on the viable yellow agouti (A^vy) mouse model, which carries a transposable element in the agouti gene. The authors test whether the metastable methylation status of specific transposable element insertion sites makes them epigenetically labile to early methyl donor nutrition. They find that dietary supplementation with folic acid, vitamin B12, choline, and betaine in dams with the a/a genotype increases CpG methylation at the A^vy locus in their A^vy/a offspring, altering their phenotype. The epigenetic metastability of this region is attributed to the A^vy transposable element. These findings suggest that dietary supplementation, which is often presumed to be beneficial, may have unintended negative effects on the establishment of epigenetic gene regulation in humans. The study highlights the importance of understanding the role of transposable elements in epigenetic regulation and the potential consequences of early nutritional interventions.The article by Waterland and Jirtle explores the hypothesis that early nutritional influences on DNA methylation can affect adult metabolism and disease susceptibility in humans and other mammals. They focus on the viable yellow agouti (A^vy) mouse model, which carries a transposable element in the agouti gene. The authors test whether the metastable methylation status of specific transposable element insertion sites makes them epigenetically labile to early methyl donor nutrition. They find that dietary supplementation with folic acid, vitamin B12, choline, and betaine in dams with the a/a genotype increases CpG methylation at the A^vy locus in their A^vy/a offspring, altering their phenotype. The epigenetic metastability of this region is attributed to the A^vy transposable element. These findings suggest that dietary supplementation, which is often presumed to be beneficial, may have unintended negative effects on the establishment of epigenetic gene regulation in humans. The study highlights the importance of understanding the role of transposable elements in epigenetic regulation and the potential consequences of early nutritional interventions.