Mother-child transmission of epigenetic information by tunable polymorphic imprinting.

Abstract

Genomic imprinting mediated by DNA methylation restricts gene expression to a single allele determined by parental origin and is not generally considered to be under genetic or environmental influence. Here, we focused on a differentially methylated region (DMR) of approximately 1.9 kb that includes a 101-bp noncoding RNA gene (<i>nc886</i>/<i>VTRNA2-1</i>), which is maternally imprinted in ∼75% of humans. This is unlike other imprinted genes, which demonstrate monoallelic methylation in 100% of individuals. The DMR includes a CTCF binding site on the centromeric side defining the DMR boundary and is flanked by a CTCF binding site on the telomeric side. The centromeric CTCF binding site contains an A/C polymorphism (rs2346018); the C allele is associated with less imprinting. The frequency of imprinting of the <i>nc886</i> DMR in infants was linked to at least two nongenetic factors, maternal age at delivery and season of conception. In a separate cohort, <i>nc886</i> imprinting was associated with lower body mass index in children at 5 y of age. Thus, we propose that the imprinting status of the <i>nc886</i> DMR is "tunable" in that it is associated with maternal haplotype and prenatal environment. This provides a potential mechanism for transmitting information, with phenotypic consequences, from mother to child.