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Methylation of DNA occurs at cytosines within CpG (cytosine-guanine) dinucleotides and is 1 of several epigenetic mechanisms that serve to establish and maintain tissue-specific patterns of gene expression. The methyl groups transferred in mammalian DNA methylation reactions are ultimately derived from methionine. High dietary methionine intake might therefore be expected to increase DNA methylation. Because of the circular nature of the methionine cycle, however, methionine excess may actually impair DNA methylation by inhibiting remethylation of homocysteine. Although little is known regarding the effect of dietary methionine supplementation on mammalian DNA methylation, the available data suggest that methionine supplementation can induce hypermethylation of DNA in specific genomic regions. Because locus-specific DNA hypomethylation is implicated in the etiology of various cancers and developmental syndromes, clinical trials of ‘promethylation’ dietary supplements are already under way. However, aberrant hypermethylation of DNA could be deleterious. It is therefore important to determine whether dietary supplementation with methionine can effectively support therapeutic maintenance of DNA methylation without causing excessive and potentially adverse locus-specific hypermethylation. In the viable yellow agouti (Avy mouse, maternal diet affects the coat color distribution of offspring by perturbing the establishment of methylation at the Avy metastable epiallele. Hence, the Avy mouse can be employed as a sensitive epigenetic biosensor to assess the effects of dietary methionine supplementation on locus-specific DNA methylation. Recent developments in epigenomic approaches that survey locus-specific DNA methylation on a genome-wide scale offer broader opportunities to assess the effects of high methionine intake on mammalian epigenomes. [ABSTRACT FROM AUTHOR]

Human epidemiologic and experimental animal studies suggest strongly that prenatal and early postnatal nutrition influence adult susceptibility to diet-related chronic disease. To elucidate biologic mechanisms linking divergent early nutritional sufficiency to adult insulin axis function in an animal model of "metabolic imprinting," this research focused on the following two objectives: 1) identify a tissue responsible for effect persistence, and 2) identify genes showing sustained differential expression in that tissue. Newborn rats were assigned randomly to small (SL), control (C) or large litters (LL) until weaning. Glucose and insulin tolerance tests were conducted directly after weaning (age 26 d) and in adulthood (ages 110 and 255 d). Glucose-stimulated insulin secretion from isolated pancreatic islets was assessed at those ages. DNA microarrays were used to identify genes showing persistent between-group differential expression in isolated islets. Glucose and insulin tolerance tests suggested persistently reduced pancreatic glucose-responsiveness in SL and LL rats. Insulin tolerance tests showed no group differences in whole-body insulin-stimulated glucose uptake. These data support the hypothesis that the endocrine pancreas contributes to primary imprinting in this model. Persistent defects in glucose-stimulated insulin secretion from isolated islets also supported this hypothesis but only in SL rats. Of 13 named islet genes showing SL vs. C differential expression at age 26 d, 10 remained differentially expressed at age 110 d. These data indicate that the endocrine pancreas plays a primary role in the putative metabolic imprinting mechanism in SL rats. [ABSTRACT FROM AUTHOR]