Breaking Rules: The complex relationship between DNA methylation and X-chromosome inactivation in the human placenta

ABSTRACT: Background: The human placenta is distinct from most organs due to its uniquely low-methylated genome. Previous research has shown that DNA methylation (DNAme) is particularly depleted in the placenta at partially methylated domains and on the inactive X chromosome (Xi) in XX samples. While Xi DNAme is known to be critical for X-chromosome inactivation (XCI) in other tissues, its role in the placenta remains unclear. Understanding X-linked DNAme variation in the placenta may provide insights into XCI and implications for prenatal development and phenotypic sex differences. Methods: DNAme data were analyzed from over 350 human placental (chorionic villus) samples, along with samples from cord blood, amnion, chorion, and fetal somatic tissues. We characterized X chromosome DNAme variation in the placenta relative to sample variables including cell composition, maternal age, placental weight, and fetal birth weight, and compared these patterns to other tissues. We also evaluated the relationship between X-linked DNAme and previously reported XCI gene expression status in placenta. Results: Our findings confirm that the placenta exhibits significant depletion of DNAme on the Xi compared to other tissues. Additionally, we observe that X chromosome DNAme profiles in the placenta are influenced by cell composition, particularly trophoblast proportions, with minimal variation across gestation. Notably, low promoter DNAme is observed at most genes on the Xi, regardless of XCI status, challenging known associations in somatic tissues between low promoter DNAme and XCI escape. Conclusions: This study provides evidence that the human placenta has a distinct Xi DNAme landscape, which may inform our understanding of sex differences during prenatal development. Future research should explore the mechanisms underlying the placenta's unique X-linked DNAme profile and the factors involved in XCI maintenance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281173 | GEO | 2025/03/12

REPOSITORIES: GEO