Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction

Abstract

Fetal growth restriction (FGR) is associated with increased susceptibility to perinatal morbidity and mortality. Evidence suggests that epigenetic changes play critical roles in the regulation of fetal growth. We sought to present a comprehensive analysis of the associations between placental DNA methylation and selective fetal growth restriction (sFGR), which is a severe complication of monochorionic twin pregnancies, characterized by one fetus experiencing restricted growth. Genome‐wide methylation analysis was performed on 24 placental samples obtained from 12 monochorionic twins with sFGR (Cohort 1) using Illumina Infinium MethylationEPIC BeadChip. Integrative analysis of our EPIC data and two previous placental methylation studies of sFGR (a total of 30 placental samples from 15 sFGR twins) was used to identify convincing differential promoter methylation. Validation analysis was performed on the placentas from 15 sFGR twins (30 placental samples), 15 FGR singletons, and 14 control singletons (Cohort 2) using pyrosequencing, quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry (IHC). A globe shift toward hypomethylation was identified in the placentas of growth‐restricted fetuses compared with the placentas of normal fetuses in monochorionic twins, including 5625 hypomethylated CpGs and 452 hypermethylated CpGs, especially in the regions of CpG islands, gene‐body and promoters. The analysis of pathways revealed dysregulation primarily in steroid hormone biosynthesis, metabolism, cell adhesion, signaling transduction, and immune response. Integrative analysis revealed a differentially methylated promoter region in the CYP11A1 gene, encoding a rate‐limiting enzyme of steroidogenesis converting cholesterol to pregnenolone. The CYP11A1 gene was validated to have hypomethylation and higher mRNA expression in sFGR twins and FGR singletons. In conclusion, our findings suggested that the changes in placental DNA methylation pattern in sFGR may have functional implications for differentially methylated genes and regulatory regions. The study provides reliable evidence for identifying abnormally methylated CYP11A1 gene in the placenta of sFGR.

Placental Malaria Induces a Unique Placental Methylation Profile Associated with Fetal Growth Restriction

“…Despite the differences in cellular composition between non-malarial FGR and PM-FGR, the differentially methylated CpGs were distinct from those associated with specific cell types. In contrast, a study that conducted the same deconvolution analysis on placentas from monochorionic twins complicated by selective FGR found decreased proportions of stromal cells with FGR compared the normally grown twin (41). This suggests a distinct placental response to FGR in twins compared with singletons.…”

“…Previous studies investigating placental epigenetic changes occurring with FGR have identified various differentially methylated CpG sites and related genes involved with fatty acid oxidation, transcriptional regulation, immune responses, cell adhesion, metabolism, cell growth (32,41–44). Our results did not have any clear overlap between the most of these studies.…”

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health

“…Interestingly, several of the genes and epigenetic loci that we identified as differentially methylated in association with increasing placental PFAS concentrations have been associated with other endocrine disrupting chemicals and with cardiometabolic outcomes. For instance, multiple CpGs within XKR6 , among other CpGs and genes, were found to have lower DNA methylation levels among placenta of newborns with selective fetal growth restriction [26]. Higher levels of maternal urinary bisphenol A (BPA) concentrations were associated with lower DNA methylation of one CpG in XKR6 [27].…”