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Methyl donors change the germline epigenetic state of the A^vy allele

Jennifer E. Cropley^*, Catherine M. Suter^* and David I. K. Martin^*,,1

^* Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; and

Children’s Hospital Oakland Research Institute, Oakland California, USA

¹Correspondence: Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. Email: dimartin{at}chori.org

Waterland and colleagues conclude that the epigenetic effect of methyl donors in A^vy mice is not inherited (1) , and contrast their result with our report of induced germline epigenetic change in A^vy (2) . There is a simple explanation for the discrepancy. A^vy mice are epigenetic mosaics: the A^vy allele is active and unmethylated in some cells, silent and methylated in others (3 , 4 ; and J.C. and D.M., unpublished). Methyl donors increase the proportion of silent A^vy alleles (2 , 5 6 7) ; inheritance of this silent state is at issue here. Yellow mice have no silent A^vy alleles, mottled mice as few as 5%. Waterland et al. bred mostly females that were either yellow or lightly mottled (i.e., in most of their cells the A^vy allele had not been silenced by methyl donors). Germ cells in these mice will reflect the somatic state of A^vy (mostly active), but epigenetic inheritance at A^vy results from germline maintenance of the silent state (4 , 8) . Heavily mottled mice, which are more likely to have silent A^vy alleles in their germline cells, were minor contributors to the breeding population.

Thus, in most of the mice bred by Waterland et al. there was little or nothing in the germline to be inherited. Our experiment (2) maximized the chances of observing epigenetic inheritance at A^vy, by breeding only pseudoagouti females (in which A^vy is completely silent in somatic cells) with or without a history of methyl donor supplementation. The result was unambiguously consistent with our conclusion that "...methyl donors can change the epigenetic state of the A^vy allele in the germline (2) ." We expect that Waterland and colleagues would have observed a small degree of inheritance, attributable largely to passage of silent A^vy through heavily mottled and pseudoagouti mice, if they had carried out their experiment with very large numbers of mice.

FOOTNOTES

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REFERENCES

1. Waterland, R. A., Travisano, M., Tahiliani, K. G. (2007) Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. [E-pub ahead of print]
2. Cropley, J. E., Suter, C. M., Beckman, K. B., Martin, D. I. (2006) Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc. Natl. Acad. Sci. U S A 103,17308-17312[Abstract/Free Full Text]
3. Duhl, D. M., Vrieling, H., Miller, K. A., Wolff, G. L., Barsh, G. S. (1994) Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8,59-65[CrossRef][Medline]
4. Morgan, H. D., Sutherland, H. G., Martin, D. I., Whitelaw, E. (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet 23,314-318[CrossRef][Medline]
5. Cooney, C. A., Dave, A. A., Wolff, G. L. (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 132,2393S-2400S[Abstract/Free Full Text]
6. Waterland, R. A., Jirtle, R. L. (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell Biol. 23,5293-5300[Abstract/Free Full Text]
7. Wolff, G. L., Kodell, R. L., Moore, S. R., Cooney, C. A. (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12,949-957[Abstract/Free Full Text]
8. Wolff, G. L. (1978) Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics 88,529-539[Abstract/Free Full Text]

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