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

## TL;DR

This study identifies genes regulated by DNA methylation in the placenta that may contribute to fetal growth restriction, a condition linked to poor pregnancy outcomes.

## Contribution

The study provides reproducible epigenetic signatures of fetal growth restriction by integrating data from two independent placental methylome datasets.

## Key findings

- 108 shared differentially methylated positions were identified across two cohorts, associated with genes involved in placental development.
- Genes like EPHA1, ANGPTL6, and CYP19A1 were linked to methylation changes affecting angiogenesis and immune regulation.
- Novel candidates such as SLC39A12 and MIR515 family members were identified as potentially epigenetically regulated in fetal growth restriction.

## Abstract

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.