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Maternal Environment May Influence Child Health Through Epigenetic Alterations

NEW YORK (GenomeWeb) – A mother's environment around the time of conception can influence the epigenome of her infant and possibly affect the child's life-long disease risk.

In a two-pronged study, researchers from the US and UK searched for metastable epialleles — patterns of methylation that are laid down in the earliest developmental stages — to examine the influence of the early environment on the epigenome. A study of two Caucasian men from the US and 120 rural Gambian infants both turned up the VTRNA2-1 gene as an environmentally responsive epiallele, as they reported yesterday in Genome Biology.

In the Gambian cohort, the researchers noted that whether the infant was conceived during the rainy or dry season — the latter being the harvest time — affected methylation levels at VTRNA2-1. As VTRNA2-1 is both a putative tumor suppressor and innate immune system modulator, there could be associated effects on health, the researchers noted.

"By studying babies conceived to mothers eating very different diets in the dry and rainy seasons in rural Gambia we could exploit a natural experiment," first author Matt Silver from the London School of Hygiene and Tropical Medicine said in a statement.

The researchers performed genome-wide bisulfite sequencing on both peripheral blood lymphocyte and hair follicle DNA samples from two healthy male Caucasian adults in the US. By comparing patterns of methylation between the tissues samples from the same men, the researchers uncovered 109 candidate metastable epialleles.

When they prioritized this set of candidate metastable epialleles by looking at genes linked to multiple nearby epialleles, the region near VTRNA2-1 stood out, the researchers reported.

In the other prong of the study, the researchers searched for regions of the genome where the epigenome changes by examining DNA methylation using an Illumina HumanMethylation450 BeadChip array in 120 Gambian infants born at different times of the year.

The top differentially methylated region by season of conception, they found, was VTRNA2-1. Further, it exhibited lower methylation in the dry versus the rainy season.

To determine whether maternal nutrition does have an effect on methylation at VTRNA2-1, the researchers examined 13 maternal nutrition biomarkers, sampled early in pregnancy, to see if they could predict VTRNA2-1 hypomethylation in the infant. Low maternal vitamin B2 and methionine levels around the time of conception, the researchers reported, could presage low VTRNA2-1 methylation levels in the infant. At the same time, low maternal plasma levels of dimethylglycine protected against low methylation levels at VTRNA2-1.

Riboflavin is required for the synthesis of flavin-adenine dinucleotide, an essential cofactor in methylenetetrahydrofolate reductase, which is a rate-limiting enzyme in one-carbon metabolism, the researchers said. Riboflavin deficiency is common, they added, in low-income populations, including rural Gambia.

Serial samples of peripheral blood lymphocyte DNA taken from 55 Gambians over the span of a decade revealed that individual methylation patterns at this locus persist over time.

"Our results show that the methylation marks that regulate how VTRNA2-1 is expressed are influenced by the season in which babies are conceived," Silver added. "Maternal nutrition is the most likely driver."

That both arms of the study homed in on the same epiallele was striking, the researchers said.

"There are around 20,000 genes in the human genome. So, for our two groups, taking different approaches, to identify this same gene as the top epiallele was like both of us digging into different sides of a gigantic haystack and finding the exact same needle," Baylor's Robert Waterland, who led the US part of the study, said.

VTRNA2-1 is thought to act as a tumor suppressor — increased methylation at that site has been linked to poor prognosis in a number of cancers — and to modulate innate immunity, so the researchers said epigenetic alterations there could affect children's health and disease.

"Because this gene plays a key role in controlling response to viral infections and offering protection against certain cancers, the potential implications are enormous," Andrew Prentice, who leads the nutrition theme of the MRC Unit in The Gambia and the MRC International Nutrition Group at the London School of Hygiene & Tropical Medicine, said.

The researchers added that they plan to follow the Gambian children to see how epigenetic differences at VTRNA2-1 affect gene expression and their health.