Placental epigenetic and transcriptional dysregulation in type I selective fetal growth restriction.

OBJECTIVE

To elucidate the epigenetic and transcriptional mechanisms underlying Type I selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies.

METHODS

Placental tissues from nine MCDA twin pairs diagnosed with Type I sFGR were analyzed using an integrative multi-omics approach, including chromatin accessibility profiling (ATAC-seq), DNA methylation microarray, and RNA sequencing. Differential analyses between the smaller (sFGR-S) and larger (sFGR-L) twin placentas were performed, and functional enrichment analyses were applied to identify key regulatory pathways and genes.

RESULTS

ATAC-seq revealed a significant reduction in global chromatin accessibility in sFGR-S placentas, with enriched differentially accessible regions in oxidative stress and metabolic pathways. DNA methylation profiling identified 4822 differentially methylated positions, with hypomethylation enriched in hypoxia-related pathways. RNA sequencing identified 654 differentially expressed genes, involved in angiogenesis (27 genes), hypoxia response (34 genes), and oxidative stress (68 genes). Multi-omics integration identified HK2 as a central upregulated gene in sFGR-S, correlating with hypoxia activity and showing strong predictive value for sFGR (AUC = 0.917). Network analysis further identified small-molecule compounds targeting HK2, including antioxidants, metabolic regulators, and polyphenols, with potential therapeutic relevance.

CONCLUSION

This study provides a comprehensive multi-omics characterization of Type I sFGR placentas, identifying HK2 as a key metabolic regulator linked to hypoxia-induced metabolic stress and oxidative damage. These findings expand our understanding of the molecular mechanisms involved in Type I sFGR. Further validation in larger cohorts is warranted to assess HK2's potential clinical utility.