Programming of the respiratory epithelium in utero - insight from the amniotic epithelial methylome

Dysregulation of the airway epithelium contributes to recurrent wheezing and asthma and may have developmental origins. Here, we investigated the relationship between the placental amniotic and nasal epithelial methylation landscapes to determine whether amniotic epithelium provides insight into fetal programming of respiratory tissue.

We conducted high-throughput target-capture DNA methylation sequencing of 84 matched pairs of placental amniotic and neonatal nasal brushings samples within the Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) cohort. Comparative analysis of tissue-specific methylation profiles, and conservation of methylation changes associated with gestational exposures (maternal smoking and maternal asthma), was explored.

Between amniotic and nasal tissues, we identified 4,897 differentially methylated regions (FDR ≤ 0.05 and log₂FC ≥ |0.2|) that were generally hypermethylated in the nasal epithelium. Despite these extensive tissue-specific differences, filtering for loci with non-significant differential methylation (FDR ≥ 0.1) revealed 1,493,976 CpG loci (~20% of the measured methylome) with highly concordant methylation ratios levels between tissues (Pearson's R ≥ 0.8). These loci included genes crucial to epithelial and lung development. Within these conserved regions, associations with maternal asthma and prenatal smoking were consistently represented in both tissues.

The conserved methylome signatures support the use of amniotic tissue as a valuable tissue for investigating the developmental programming of airway vulnerability, potentially leading to early risk stratification and targeted interventions for childhood asthma.