Prospective epigenome and transcriptome analyses of cord and peripheral blood from preterm infants at risk of bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil–lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.

Macrophage Polarizations in the Placenta and Lung are Associated with Bronchopulmonary Dysplasia

“…Analysis conducted using the C#13 SMaRT model indicates an association between BPD and tolerant states specifically within the intermediate monocyte subset (Fig 3b), contrasting with no such association observed in the classical monocyte subset (Fig 3c). This trend persisted across three additional publicly available datasets, including cord blood (GSE220135) 21 and peripheral blood mononuclear cells (PBMC) (GSE125873, GSE108754), 22, 23 consistently demonstrating that BPD is linked to tolerant states of macrophages (Fig 3d-f). These collective results underscore the robust and consistent association between BPD and the induction of tolerant macrophage states.…”

Antimicrobial Peptides (AMPs) and the Microbiome in Preterm Infants: Consequences and Opportunities for Future Therapeutics

“…Exposure to an inflammatory environment also contributes to lung impairment [ 14 , 15 , 16 , 17 , 18 ]. In the postnatal course, up to 50% of premature babies develop a phenotype of chronic lung disease, i.e., bronchopulmonary dysplasia (BPD) [ 19 ].…”