Mother–child transmission of epigenetic information by tunable polymorphic imprinting

TY - JOUR

T1 - Mother–child transmission of epigenetic information by tunable polymorphic imprinting

AU - Carpenter, Brittany L.

AU - Zhou, Wanding

AU - Madaj, Zachary

AU - DeWitt, Ashley K.

AU - Ross, Jason P.

AU - Grønbæk, Kirsten

AU - Liang, Gangning

AU - Clark, Susan J.

AU - Molloy, Peter L.

AU - Jones, Peter A.

PY - 2018

Y1 - 2018

N2 - 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 (nc886/VTRNA2-1), 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 nc886 DMR in infants was linked to at least two nongenetic factors, maternal age at delivery and season of conception. In a separate cohort, nc886 imprinting was associated with lower body mass index in children at 5 y of age. Thus, we propose that the imprinting status of the nc886 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.

AB - 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 (nc886/VTRNA2-1), 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 nc886 DMR in infants was linked to at least two nongenetic factors, maternal age at delivery and season of conception. In a separate cohort, nc886 imprinting was associated with lower body mass index in children at 5 y of age. Thus, we propose that the imprinting status of the nc886 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.

KW - DNA methylation

KW - Epigenetic inheritance

KW - Nc886

KW - Polymorphic imprinting

KW - VTRNA2-1

U2 - 10.1073/pnas.1815005115

DO - 10.1073/pnas.1815005115

M3 - Journal article

C2 - 30509985

AN - SCOPUS:85058677880

SN - 0027-8424

VL - 115

SP - E11970-E11977

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 51

ER -