The human placental methylome

Abstract

This review provides an overview of the unique features of DNA methylation in the human placenta. We discuss the importance of understanding placental development, structure, and function in the interpretation of DNA methylation data. Examples are given of how DNA methylation is important in regulating placental-specific gene expression, including monoallelic expression and X-chromosome inactivation in the placenta. We also discuss studies of global DNA methylation changes in the context of placental pathology and environmental exposures.

Figure 1.

Correlation dendrogram of DNA methylation at 473,369 CpG sites. Correlation dendogram using Illumina HumanMethylation450 BeadChip data filtered for X and Y chromosome probes, probes cross-hybridizing to the X or Y, probes with SNPs in the target CpG site and probes that could not be distinguished from the background signal (detection p value >0.05). Sample sizes for each tissue group are: 3 female cord blood, 10 maternal blood, 3 decidua, 6 female cultured CVS (chorionic villus sampling), 3 female and 3 male umbilical cord, 3 male amnion, 7 female and 6 male muscle, 8 female and 7 male kidney, 4 female and 5 male spinal cord, 6 female and 5 male brain, 4 FACS-sorted cytotrophoblast, 2 female and 3 male first trimester chorionic villi (<13 wk gestation), 8 female and 6 male second trimester chorionic villi (≥13 to <24 wk gestation), 10 female and 11 male term chorionic villi (≥37 wk gestation), 5 density-gradient separated term cytotrophoblast. *Indicates a pooled sample of several individuals. Colored labels indicate the origin of each tissue.

Figure 2.

Applications of placental DNA methylation. (A) DNA methylation at imprinting control regions (ICRs) such as those associated with the genes SGCE and H19 can be used to identify genomic imbalance in the placenta. Mean and standard deviation of DNA methylation levels for digynic and diandric triploidy and controls are indicated. (Adapted from Bourque et al. 2010.) (B) Regions of the genome with distinct patterns of placental DNA methylation as compared with that in maternal blood, for example at the CpG island of RASSF1 depicted here, can be used to distinguish fetal DNA in maternal circulation. Each data point represents the mean level of DNA methylation at a single CpG site obtained from the Illumina HumanMethylation450 BeadChip array; error bars represent standard deviation of the mean (WP Robinson and EM Price, unpubl.). (C) Altered DNA methylation may be detected in the placentas of complicated pregnancies, such as in early onset preeclampsia (EOPET). These may not be restricted to CpG islands; in TIMP3 (chr22: 33195342–33257640), for example, lower DNA methylation is observed in the putative enhancer region. Each data point represents the mean level of DNA methylation at a single CpG site obtained from the Illumina HumanMethylation450 BeadChip array; error bars represent standard deviation of the mean. (Adapted from Blair et al. 2013.) DNA methylation, DNAme.