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Genome-Wide Analysis of DNA Methylation in Hyperoxia-Exposed Newborn Rat Lung
Chung-Ming Chen1,2, Yi-Chun Liu3, Yue-Jun Chen3
1Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan. cmchen@tmu.edu.tw.
Insights
Neonatal hyperoxia exposure arrests lung development by altering DNA methylation, affecting key pathways like actin cytoskeleton and focal adhesion. This epigenetic disruption delays alveolarization, similar to bronchopulmonary dysplasia in infants.
Area of Science:
- Neonatology
- Pulmonary Medicine
- Epigenetics
Background:
- Oxygen therapy is crucial for newborns with respiratory issues.
- Neonatal hyperoxia causes lung damage resembling human bronchopulmonary dysplasia.
- Epigenetic regulation is vital in bronchopulmonary dysplasia development.
Purpose of the Study:
- To investigate the epigenetic mechanisms of hyperoxia-induced lung injury in neonatal rats.
- To identify changes in DNA methylation patterns associated with arrested alveolarization.
Main Methods:
- Neonatal rats were exposed to room air or 85% oxygen from postnatal days 1-14.
- Genome-wide DNA methylation was analyzed using Methylated DNA Immunoprecipitation (MeDIP) and next-generation sequencing.
- Bioinformatics and pathway analyses identified differentially methylated genes and affected signaling pathways.
Main Results:
- Neonatal hyperoxia arrested alveolarization by postnatal day 14.
- Hyperoxia exposure led to larger air spaces and thinner septa.
- Epigenetic modulation of ErbB, actin cytoskeleton, and focal adhesion pathways was observed.
Conclusions:
- Aberrant DNA methylation and pathway deregulation contribute to hyperoxia-induced arrested alveolarization.
- These findings highlight the role of epigenetics in neonatal lung injury.
Purpose:
Oxygen therapy is often required to treat newborn infants with respiratory disorders. Prolonged exposure of neonatal rats to hyperoxia reduced alveolar septation, increased terminal air space size, and increased lung fibrosis; these conditions are very similar to those of human bronchopulmonary dysplasia. Epigenetic regulation of gene expression plays a crucial role in bronchopulmonary dysplasia development.
Method:
We reared Sprague-Dawley rat pups in either room air (RA, n = 24) or an atmosphere containing 85% O2 (n = 26) from Postnatal Days 1 to 14. Methylated DNA immunoprecipitation (MeDIP) was used to analyze genome-wide DNA methylation in lung tissues of neonatal rats. Hyperoxia-exposed rats exhibited larger air spaces and thinner septa than RA-exposed rats did on Postnatal Day 14. The rats exposed to hyperoxia exhibited significantly higher mean linear intercepts than did the rats exposed to RA. We applied MeDIP next-generation sequencing for profiling changes in DNA methylation in the rat lungs exposed to hyperoxia and RA. We performed bioinformatics and pathway analyses on the raw sequencing data to identify differentially methylated candidate genes.
Results:
Our in vivo model revealed that neonatal hyperoxia exposure arrested alveolarization on Postnatal Day 14. We found that the ErbB, actin cytoskeleton, and focal adhesion signaling pathways are epigenetically modulated by exposure to hyperoxia. We demonstrated that hyperoxia exposure contribute in delaying lung development through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in alveolarization.
Conclusions:
These data indicate that aberrant DNA methylation and deregulation of the actin cytoskeleton and focal adhesion pathways of lung tissues may be involved in the pathophysiology of hyperoxia-induced arrested alveolarization.
