Decoding bronchopulmonary dysplasia in premature infants through an epigenetic lens

Abstract

This review provides a comprehensive overview of the evolving insights into the epigenetic mechanisms associated with bronchopulmonary dysplasia (BPD). It specifically highlights the roles of DNA methylation, histone modifications, and RNA regulation in the development of BPD in premature infants. BPD results from complex interactions among genetic factors, environmental exposures, and neonatal stressors. Key findings suggest that intrauterine hypoxia, hyperoxia, and nutrition can lead to epigenetic alterations, affecting gene expression and methylation, which may serve as biomarkers for early BPD detection. RUNX3 is identified as a critical transcription factor influencing lung development and inflammation, while changes in DNA methylation and histone dynamics in cord blood are linked to immune dysregulation associated with BPD. The role of m6A RNA methylation regulators from the IGF2BP family affects mRNA stability and gene expression relevant to BPD. Additionally, specific histones and microRNAs, particularly from the miR-17∼92 cluster, are implicated in pulmonary development and vascular regulation. Long non-coding RNAs (lncRNAs), such as MALAT1, also play a role in gene regulation via competitive endogenous RNA networks, indicating their potential as biomarkers and therapeutic targets. The interplay of these epigenetic mechanisms underscores the need for further research to develop targeted interventions aimed at reducing BPD severity and enhancing health outcomes for at-risk neonates.

Keywords: DNA methylation; RUNX3; bronchopulmonary dysplasia; epigenetics; long non-coding RNAs; microRNAs.

FIGURE 1

The epigenetic program regulates bronchopulmonary dysplasia (BPD) development. Intrauterine hypoxia triggers various epigenetic mechanisms that coordinate lung plasticity. This results in inflammation during lung development, inhibiting the growth of alveoli and blood vessels. Consequently, the balance between normal and abnormal lung development is disrupted, leading to BPD. Epigenetic therapies utilizing DNMT inhibitors, histone deacetylase (HDAC) inhibitors, and miR modulators can enhance lung development and mitigate the onset of neonatal chronic lung disease. This figure is derived from a study by Tong et al. (10).

FIGURE 2

Overview of cord blood genes and pathways linked to bronchopulmonary dysplasia (BPD) and a comparison of epigenetic changes. (A) The dot plot illustrates enriched pathways and gene ontology (GO) terms from differentially expressed genes in BPD cases versus non-BPD controls, with pathway analysis adjusted for covariates like cell type proportions, sex, gestational age, and birth weight. Pathways related to cord blood epigenome-wide association studies (EWAS) are highlighted for their relevance to BPD. Circle size represents pathway or GO significance, while color indicates activation trends. (B) Ingenuity Pathway Analysis (IPA) identifies interleukin 2 (IL-2) as a crucial factor influencing epigenomic and transcriptomic changes in blood cell development and function during BPD pathogenesis. Key molecules in this network—SIRT1, TREX1, and IRF2—play roles in regulating cytokine signaling and transcription, potentially impacting BPD progression. This figure is derived from a study by Cho et al. (21).