DNA methylation and hydroxymethylation combined with transcriptional profiling identify key regulators of hyperoxia-induced bronchopulmonary dysplasia

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BACKGROUND: Hyperoxia-induced bronchopulmonary dysplasia (BPD) is a major cause of lung injury in premature infants. Epigenetics, particularly DNA (hydroxy)methylation, has been identified as a crucial regulator of BPD pathogenesis. This study aimed to reveal key regulators and pathogenic genes involved in hyperoxia-induced BPD via DNA (hydroxy)methylation and transcriptional analysis. METHODS AND RESULTS: Multi-omics analyses including RNA-seq, reduced representation bisulfite sequencing (RRBS), and oxidative RRBS (oxRRBS) were conducted on lung tissues from hyperoxia-induced rat BPD model. Differentially methylated and hydroxymethylated regions (DMRs and DhMRs) were further detected by targeted bisulfite sequencing (TBS) and oxidative TBS (oxTBS). Differentially expressed genes (DEGs) were finally verified in hyperoxia-exposed lung tissues by qPCR, western blotting, and immunohistochemistry. Our integrated analysis identified 2058 DEGs, 62,123 DMRs, and 33,212 DhMRs in hyperoxia-induced BPD. Among them, eighteen candidate genes with altered expression patterns were revealed to be involved in BPD-related pathways. Notably, ten candidate genes, including Cxcl6, Gpr39, Hs6st2, Htatip2, Apln, Calca, Hist1h1t, Lgals3, Rarres1, and Rasl2-9, exhibited significant upregulation with both hypo-DNA methylation and hyper-DNA hydroxymethylation levels. Conversely, eight candidate genes, containing Krt76, Spon2, Abcc6, Egfl7, Gpbar1, Myh6, Tgfbi, and Tmem100, displayed pronounced downregulation associated with both hyper-DNA methylation and hypo-DNA hydroxymethylation levels. Most importantly, the upregulation of Apln and Calca was further validated in hyperoxia-induced BPD, which was characterized by reduced DNA methylation and increased DNA hydroxymethylation levels at their promoter regions. CONCLUSIONS: This study reveals that hyperoxia triggers decreased DNA methylation together with increased DNA hydroxymethylation at promoter regions of Apln and Calca, promoting their gene expression and contributing to BPD pathogenesis.

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