Integrative Analysis of Placental Methylomes Identifies Epigenetically Regulated Genes Implicated in Fetal Growth...

Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from an in-house early-onset FGR cohort and compared them with a publicly available dataset (GSE100197). DNA methylation profiling was performed using Illumina EPIC (in-house) and 450K (public) arrays, processed with identical normalization and quality-control pipelines, including adjustment for gestational age and estimation of placental cell-type composition. Differentially methylated positions (DMPs) were identified using linear regression models, revealing 10,427 DMPs in the in-house cohort and 7467 in the public dataset, with 108 shared DMPs showing consistent direction of change across both cohorts. Promoter-associated DMPs were mapped to genes involved in angiogenesis, morphogenesis, immune regulation, and transcriptional control, including EPHA1, ANGPTL6, ITGAX, BCL11B, and CYP19A1, while additional novel candidates such as SLC39A12, YEATS4, and MIR515 family members were also identified. Functional annotation suggests that these methylation changes may influence pathways essential for placental vascular development and structural organization. Overall, this cross-cohort comparison highlights reproducible epigenetic signatures of FGR and underscores the need for standardized approaches to clarify the molecular mechanisms underlying placental insufficiency.