Maternal nutrition at conception modulates DNA methylation of human metastable epialleles

Paula Dominguez-Salas, Sophie E Moore, Maria S Baker, Andrew W Bergen, Sharon E Cox, Roger A Dyer, Anthony J Fulford, Yongtao Guan, Eleonora Laritsky, Matt J Silver, Gary E Swan, Steven H Zeisel, Sheila M Innis, Robert A Waterland, Andrew M Prentice, Branwen J Hennig, Paula Dominguez-Salas, Sophie E Moore, Maria S Baker, Andrew W Bergen, Sharon E Cox, Roger A Dyer, Anthony J Fulford, Yongtao Guan, Eleonora Laritsky, Matt J Silver, Gary E Swan, Steven H Zeisel, Sheila M Innis, Robert A Waterland, Andrew M Prentice, Branwen J Hennig

Abstract

In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles.

Figures

Figure 1. Seasonal differences in plasma biomarker…
Figure 1. Seasonal differences in plasma biomarker concentrations.
(a) Heatmap of seasonal variation in maternal plasma biomarker concentrations at the time of conception. Columns correspond to pregnant women (main group), grouped according to season of conception. Colours represent deviation from all season mean biomarker concentrations, calculated as z-scores. Biomarkers are ranked by mean seasonal difference (Supplementary Table 2), with the greatest increment in the rainy versus dry season (BET:DMG) at the top, and the greatest decrement (SAH) at the bottom. Analysis of variance P-values: *<0.05; **<0.01; ***<0.001; N=167. (b) Comparison of seasonal patterns in the plasma biomarker concentrations between the indicator group (N=30, shown in black) and the main group before back extrapolation (N=167 total; rainy season (green), dry season (yellow)) for BET:DMG and SAM:SAH ratios, FOL, B2, MET, HCY, DMG and SAH. Y-axis units: FOL and SAH nmol l−1; in MET, HCY and DMG μmol l−1; B2 in 1 EGRAC−1. Thick line, mean of logarithm of the biomarker; thin lines, 95%CI. Plots for the remaining biomarkers are shown in Supplementary Fig. 1. B2 (riboflavin) is represented as the reciprocal of the erythrocyte glutathione reductase activation coefficient (EGRAC), a functional test inversely associated with red blood cell riboflavin sufficiency.
Figure 2. Examples of verification of metastable…
Figure 2. Examples of verification of metastable epialleles in humans.
(a) Pearson correlation of PBL DNA methylation at ZFYVE28 within 25 pairs of MZ twins shows that most interindividual variation in DNA methylation is not explained by genetics. (The inset shows the genomic region; the grey bar below the gene indicates a CpG island, and the asterisk the location of the pyrosequencing assay.) (b) Clonal bisulfite sequencing of discordant twin pair 10066 (circled in (a)). Each row represents an individual clone from the post-bisulfite PCR product, and each column a CpG site. Filled circles indicate methylation. The ~500 bp region analyzed is indicated by the line above the gene in (a). Not only the degree but also the CpG site-specific pattern of methylation is highly discordant between the two isogenic individuals. (c) Pearson correlation of PBL DNA methylation for ZNF678 within 25 MZ twin pairs again illustrates that interindividual variation is not genetically mediated. (d) Clonal bisulfite sequencing of discordant twin pair 10943 (circled in (c)). (e) DNA methylation is highly correlated between PBL and HF across all MEs (excluding PARD6G, average Pearson correlation coefficient r=0.72, range 0.39 (ZNF678) to 0.87 (LOC654433)), N=82 paired Gambian PBL and HF samples). PBL originate from mesodermal and HF from ectodermal germ layers of the early embryo; thus these data confirm that the systemic interindividual variation demonstrated in Vietnamese adults (Supplementary Fig. 2) generally extends to these Gambian children.
Figure 3. Season of conception affects DNA…
Figure 3. Season of conception affects DNA methylation at MEs.
(a) Percent methylation at the six MEs in PBL of infants conceived in the dry or rainy season. Median % methylation is consistently higher in infants conceived in the rainy season. (b) Mean PBL methylation z-score across the six MEs is significantly higher in infants conceived in the rainy season. (c) Percent methylation at the six MEs in HF of infants conceived in the dry or rainy season; the overall pattern of methylation is similar to that observed in PBL, as is the seasonal difference in mean methylation z-score (d). Box plots represent the median (horizontal line) and interquartile range (box) of the indicated distribution. The whiskers extend from the top/bottom of the box to the highest/lowest data value that is within 1.5. Asterix represents interquartile range of the box. Data beyond the whiskers are plotted as individual points. PBL, peripheral blood lymphocyte; Oneway analysis of variance P-values: *<0.05, **<0.01; PBL Nmax=126 and HF Nmax=87 infant DNA samples.

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