Fig. 8.

Potential mechanisms for environmental influences on developmental establishment of DNA methylation. A, Nutritional or other stimuli that affect either the efficiency of one-carbon metabolism or the activity of DNMT1 could alter the developmental establishment of DNA methylation at metastable epialleles. Flux through the transmethylation/remethylation pathway is dependent upon nutrients including folate, vitamins B₁₂ and B₆, choline, betaine, and methionine. B, Transcriptional activity during critical developmental periods can impair de novo methylation. Any nutritional or other environmental exposure that activates gene transcription during periods of de novo CpG methylation can permanently imprint transcriptional competence by preventing hypermethylation. Methylated CpG sites are shown as “filled lollipops.” Although a gene promoter region is shown here, similar effects could occur at any genomic region contributing to transcriptional regulation, such as a distal enhancer. 5CH3THF, 5-Methyl tetrahydrofolate; SAH, S-adenosylhomocysteine; DMG, dimethyl glycine. [Reprinted with permission from R. A. Waterland and K. B. Michels: Annu Rev Nutr 27:363–388, 2007 (55). © Annual Reviews.]