Maternal epigenetics and methyl supplements affect agouti gene expression in A^vy/a mice

^a Division of Biochemical Toxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, USA
^b Division of Biometry and Risk Assessment, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, USA
^c Division of Molecular Epidemiology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, USA
^d Departments of Biochemistry/Molecular Biology and Pharmacology/Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
^e The Bionetics Corporation, Jefferson, Arkansas 72079, USA

`Viable yellow' (A^vy/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epigenetic mosaics ranging from a yellow phenotype with maximum ectopic agouti overexpression, through a continuum of mottled agouti/yellow phenotypes with partial agouti overexpression, to a pseudoagouti phenotype with minimal ectopic expression. Pseudoagouti A^vy/a mice are lean, healthy, and longer lived than their yellow siblings. Here we report that feeding pregnant black a/a dams methyl-supplemented diets alters epigenetic regulation of agouti expression in their offspring, as indicated by increased agouti/black mottling in the direction of the pseudoagouti phenotype. We also present confirmatory evidence that epigenetic phenotypes are maternally heritable. Thus A^vy expression, already known to be modulated by imprinting, strain-specific modification, and maternal epigenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epigenetic mechanisms, especially DNA methylation, in developing embryos.—Wolff, G. L., Kodell, R. L., Moore, S. R., Cooney, C. A. Maternal epigenetics and methyl supplements affect agouti gene expression in A^vy/a mice. FASEB J. 12, 949–957

Key Words: maternal diet • methyl supplementation • DNA methylation • epigenetic regulation of gene expression • yellow mice

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