In emphasized. The evidence for epigenetic GW9662 site modification as a significant modulator of obesity and related diseases compels a deeper examination of exposure to environmental factors that may affect gene expression, particularly during periods of genetic plasticity, that is, from conception through early childhood. By exploring the strength of the biologic evidence surrounding the contributions of early-life experiences in conjunction with genetic processes to childhood obesity, BMS-214662 chemical information unique opportunities to identify potentially plastic periods ripe for prevention strategies could be uncovered. Nutritional influences on human developmental epigenetics Robert A. Waterland (Baylor College of Medicine/USDA/ARS Children’s Nutrition Research Center) discussed the developmental origins hypothesis, which proposes that, during critical periods of development, environmental stimuli guide ontogenic processes, leading to persistent alterations in metabolism and risk of disease. Of various potential mechanisms that could mediate such developmental plasticity,54 induced alterations in epigenetic gene regulation have attracted the most attention in recent years. DNA methylation occurs predominantly at palindromic CpG dinucleotides in mammals. Genomic patterns of CpG methylation, once established during development, are highly stable, affording an outstanding candidate mechanism to explain the life-scale persistence that is the hallmark of the developmental origins paradigm. However, significant obstacles have impeded progress toward testing the hypothesis that epigenetic mechanisms mediate developmental programming, said Waterland, including the inherent cell-type specificity of most epigenetic marks, the influence of genetics on interindividual epigenetic variation, and the potential for reverse causality (i.e., a disease causes epigenetic changes and vice versa).55 Importantly, a select class of genomic loci, metastable epialleles (MEs), circumvents these obstacles. At Mes, establishment of epigenotype occurs stochastically in the early embryo, but then is maintained and propagated stably to all tissue lineages during subsequent differentiation. This leads to systemic inter-individual variation in DNA methylation that is not genetically mediated. Waterland described his group’s earlier studies in murine ME models, including agouti viable yellow (Avy)56 and AxinFused,57 which found that stochastic establishment of epigenotype at Mes is particularly sensitive to maternal nutrition before and during pregnancy. To identify genomic regions in the human genome with systemic inter-individual variation in epigenetic regulation, Waterland discussed a reduced-representation method for genomescale DNA-methylation profiling. Comparing methylation profiles in both peripheral bloodAnn N Y Acad Sci. Author manuscript; available in PMC 2016 July 01.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptWahlqvist et al.Pagelymphocytes (PBLs) and hair follicle (HF) DNA from healthy Caucasian adults identified a small set of candidate MEs.58 Systemic inter-individual variation in DNA methylation was confirmed by studying liver, kidney, and brain tissues of Vietnamese cadavers, and studies in monozygotic twins demonstrated that such variation occurred even in the absence of genetic variation.58,59 To test for effects of maternal periconceptional nutritional status, Waterland teamed up with Andrew Prentice and his colleagues, who have for decades been studying.In emphasized. The evidence for epigenetic modification as a significant modulator of obesity and related diseases compels a deeper examination of exposure to environmental factors that may affect gene expression, particularly during periods of genetic plasticity, that is, from conception through early childhood. By exploring the strength of the biologic evidence surrounding the contributions of early-life experiences in conjunction with genetic processes to childhood obesity, unique opportunities to identify potentially plastic periods ripe for prevention strategies could be uncovered. Nutritional influences on human developmental epigenetics Robert A. Waterland (Baylor College of Medicine/USDA/ARS Children’s Nutrition Research Center) discussed the developmental origins hypothesis, which proposes that, during critical periods of development, environmental stimuli guide ontogenic processes, leading to persistent alterations in metabolism and risk of disease. Of various potential mechanisms that could mediate such developmental plasticity,54 induced alterations in epigenetic gene regulation have attracted the most attention in recent years. DNA methylation occurs predominantly at palindromic CpG dinucleotides in mammals. Genomic patterns of CpG methylation, once established during development, are highly stable, affording an outstanding candidate mechanism to explain the life-scale persistence that is the hallmark of the developmental origins paradigm. However, significant obstacles have impeded progress toward testing the hypothesis that epigenetic mechanisms mediate developmental programming, said Waterland, including the inherent cell-type specificity of most epigenetic marks, the influence of genetics on interindividual epigenetic variation, and the potential for reverse causality (i.e., a disease causes epigenetic changes and vice versa).55 Importantly, a select class of genomic loci, metastable epialleles (MEs), circumvents these obstacles. At Mes, establishment of epigenotype occurs stochastically in the early embryo, but then is maintained and propagated stably to all tissue lineages during subsequent differentiation. This leads to systemic inter-individual variation in DNA methylation that is not genetically mediated. Waterland described his group’s earlier studies in murine ME models, including agouti viable yellow (Avy)56 and AxinFused,57 which found that stochastic establishment of epigenotype at Mes is particularly sensitive to maternal nutrition before and during pregnancy. To identify genomic regions in the human genome with systemic inter-individual variation in epigenetic regulation, Waterland discussed a reduced-representation method for genomescale DNA-methylation profiling. Comparing methylation profiles in both peripheral bloodAnn N Y Acad Sci. Author manuscript; available in PMC 2016 July 01.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptWahlqvist et al.Pagelymphocytes (PBLs) and hair follicle (HF) DNA from healthy Caucasian adults identified a small set of candidate MEs.58 Systemic inter-individual variation in DNA methylation was confirmed by studying liver, kidney, and brain tissues of Vietnamese cadavers, and studies in monozygotic twins demonstrated that such variation occurred even in the absence of genetic variation.58,59 To test for effects of maternal periconceptional nutritional status, Waterland teamed up with Andrew Prentice and his colleagues, who have for decades been studying.