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Genetic, Environmental Factors Influence Imprinting at Differentially Methylated Noncoding Gene

NEW YORK (GenomeWeb) – Both genetic and environmental factors influence imprinting at a differentially methylated noncoding RNA gene, according to a new study.

Genomic imprinting, a type of allele-specific DNA methylation, is typically thought to be determined by parental origin. But, previous work found a unique pattern of DNA methylation at the noncoding nc886 gene: it exhibited allele-specific DNA methylation in about 75 percent of people, but is unmethylated in about 25 percent of people.

Researchers led by the Van Andel Research Institute's Peter Jones analyzed the region containing this gene and found that a polymorphism at a CTCF binding site appears to influence the level of imprinting. They further noted that non-genetic parental factors like maternal age and conception season were also linked to imprinting frequency.

"[W]e show that variation of imprinting in the population is associated with prenatal environment," Jones and his colleagues wrote in their paper, which appeared yesterday in the Proceedings of the National Academy of Sciences.

Nc886 is an RNA polymerase II-transcribed noncoding RNA that is found throughout higher-order primates. Its expression is regulated by DNA methylation, and while it is monoallelically methylated in most people, it is biallelically unmethylated in certain individuals.

The researchers compared DNA methylation at known imprinted differentially methylated regions (DMRs) gauged using Illumina's Infinium Human Methylation 450 array and peripheral blood samples from 2,664 European and Indian Asian individuals from the London Life Sciences Prospective Population (LOLIPOP) study, From that, they found that all other imprinted differentially methylated regions — excepted for nc886 — have limited inter-individual variance.

They further examined nc886, the maternally methylated DMR PEG3, and the paternally methylated DMR H19 in two studies of sperm DNA as well as peripheral blood from the LOLIPOP study. For PEG3, H19, and nc886, the researchers saw about 50 percent methylation in peripheral blood, as they expected for imprinted loci. In the sperm dataset, H19 was fully methylated, while PEG3 and nc886 were not. This indicated that the methylation at nc886 was maternally derived.

They further traced the boundaries of the nc886 DMR to two CTCF sites.

When the researchers re-analyzed data that had been collected in twin studies, they found that monozygotic twins were more likely than dizygotic twins to be concordant for DNA methylation at the nc886 DMR, suggesting that genetic factors could affect methylation there. They found that an A/C SNP at one of those CTCF binding site influenced imprinting: the A allele was associated with higher average methylation than the C allele. This suggested to the researchers that the genetic background could "tune" the likelihood of imprinting at nc886.

The researchers also examined data from three other studies and teased out additional factors that influence nc886 imprinting.

Previously, a team of investigators looking at a cohort of children from the Gambia had found that the season in which children were conceived affected their methylation status at certain genes. Here, the researchers used that data to further note that the season in which the children were conceived also influenced imprinting at nc886. Likewise, in an additional cohort, the researchers found that maternal age influenced imprinting, with younger mothers being linked to a decreased likelihood of imprinting at nc886.

The researchers also used data collected in a blood spot study to tie imprinting at nc886 to lower BMI at age five. This, they added, suggested that the prenatal environment could influence imprinting.

"A further understanding of causality from all of these observations will require an unraveling of potential biological roles of nc886 or the nc886 DMR," the researchers added.