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Title: Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female

Author
item Waterland, Robert
item TRAVISANO, MICHAEL - UNIV MINN
item TAHILIANI, KAJAL - BAYLOR COLLEGE MED

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/20/2007
Publication Date: 10/1/2007
Citation: Waterland, R.A., Travisano, M., Tahiliani, K.G. 2007. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. Journal of Federation of American Societies for Experimental Biology. 21(12):3380-3385.

Interpretive Summary: Previous studies show that maternal nutrition before and during pregnancy can affect the establishment of genetic changes at the mouse gene site known as agouti viable yellow. Also, the agouti viable yellow gene is special in that transgenerational inheritance of epigenetic information appears to occur at the locus. Hence, we conducted a three-generation cumulative exposure study to determine if diet effects on genetic changes (DNA methylation) at agouti viable yellow are inherited transgenerationally. We show that diet-induced genetic changes at this gene site are not inherited. Our results indicate that transgenerational epigenetic inheritance at agouti viable yellow likely involves multiple molecular mechanisms in addition to DNA methylation.

Technical Abstract: The effects of nonmutagenic environmental exposures can sometimes be transmitted for several generations, suggesting transgenerational inheritance of induced epigenetic variation. Methyl donor supplementation of female mice during pregnancy induces CpG hypermethylation at the agouti viable yellow (A(vy)) allele in A(vy)/a offspring. Epigenetic inheritance occurs at A(vy); when passed through the female germ line, A(vy) epigenotype is not completely "reset." We therefore tested whether diet-induced epigenetic alterations at A(vy) are inherited transgenerationally. Female A(vy)/a mice were weaned onto either control (n=6) or a methyl-supplemented diet (n=5). These F0 dams were mated with a/a males. All F1 and F2 A(vy)/a females were weaned onto the same diet as their mothers, then mated with a/a males. F1, F2, and F3 A(vy)/a offspring were classified for coat color, an indicator of A(vy) methylation. In total, 62 F1, 98 F2, and 209 F3 A(vy)/a mice were studied. As expected, average A(vy)/a coat color was darker in the supplemented group (P<0.01). However, there was no cumulative effect of supplementation across successive generations. These results suggest that, in the female germ line, diet-induced A(vy) hypermethylation occurs in the absence of additional epigenetic modifications that normally confer transgenerational epigenetic inheritance at the locus.