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Summary The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named “metastable epialleles” could in principle explain this “missing heritability.” We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene ( POMC ), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation. [ABSTRACT FROM AUTHOR]

Background: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season. Objective: The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers. Design: In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly. Results: Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season. Conclusions: Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641. [ABSTRACT FROM AUTHOR]

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]

Focuses on the synthesis of a subset of a human epidemiologic and experimental animal studies that suggest that early nutrition affects susceptibility to chronic diseases in adulthood. Possible existence of biological mechanisms that `memorize' the metabolic effects of early nutritional environments; Proposal for a working definition of metabolic imprinting.

IR spectra for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8) were recorded in 700Torr of air, 298±2K. Integrated absorption cross sections (650–1800cm−1) of (1.18±0.06), (1.32±0.07), (2.43±0.12), (2.86±0.14) and (3.32±0.17)×10−16cm2molecule−1cm−1 were determined for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8), respectively. Radiative efficiencies of 0.159, 0.176, 0.338, 0.376, and 0.418Wm−2ppb−1 were calculated for CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8), respectively. The title compounds have short atmospheric lifetimes (approximately 7–8 days) and 100-year global warming potentials of ≤2. CxF2x+1CHᆖCH2 (x=1, 2, 4, 6, 8) will not contribute significantly to radiative forcing of climate change. [Copyright &y& Elsevier]

Comments on the article by Cooney and others about the potential for metabolic imprinting to occur through epigenetic mechanisms. Perception of the importance of epigenetics to understanding diet-health relationships; Effects of maternal dietary methyl supplementation on the coat color distribution of heterozygous.

Objective: To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring.Design: Microarray analysis of DNA methylation in archived neonatal bloodspots of in vitro fertilization (IVF)/ICSI-conceived children compared with controls born to fertile and infertile parents.Setting: Academic research laboratory.Patient(s): Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer.Intervention(s): None.Main Outcome Measure(s): The Illumina Infinium HumanMethylation450k BeadChip assay determined genome-wide DNA methylation. Methylation differences between conception groups were detected using a Bioconductor package, ChAMP, in conjunction with Adjacent Site Clustering (A-clustering).Result(s): The methylation profiles of assisted reproductive technology and IUI newborns were dramatically different from those of naturally (in vivo) conceived newborns. Interestingly, the profiles of ICSI-frozen (FET) and IUI infants were strikingly similar, suggesting that cryopreservation may temper some of the epigenetic aberrations induced by IVF or ICSI. The DNA methylation changes associated with IVF/ICSI culture conditions and/or parental infertility were detected at metastable epialleles, suggesting a lasting impact on a child's epigenome.Conclusion(s): Both infertility and ICSI alter DNA methylation at specific genomic loci, an effect that is mitigated to some extent by FET. The impact of assisted reproductive technology and/or fertility status on metastable epialleles in humans was uncovered. This study provides an expanded set of loci for future investigations on IVF populations. [ABSTRACT FROM AUTHOR]