Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

Abstract

DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-b signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.Keywords: lung development; premature infant; epigenetics; bronchopulmonary dysplasia Clinical RelevanceDNA methylation is an important regulator of gene expression. Coordinated expression of multiple genes occurs at specific time points during alveolar septation in lung development. In this study, we identified multiple genes that are potentially regulated by DNA methylation during normal alveolar septation in the mouse and human lung, and in bronchopulmonary dysplasia compared to preterm or term lung.

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

“…Subsequently, however, genome wide association studies were unable to identify single nucleotide polymorphisms significantly associated with an increased risk of BPD 165, 166 . Additional screens to detect epigenetic marks 167 and changes in long non-coding RNA 168 , have recently been performed, and others such as proteomic and metabolomic screens, have not yet been undertaken. Although these advances in high throughput, ‘omic’ technologies can yield vast amounts of data, heterogeneity in the diseased population and the presence of multiple confounding factors can limit the power to differentiate true signals from background noise.…”

Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases

“…A recent study has shown that 23 genes are differentially methylated with reciprocal changes in expression in patients with BPD compared with preterm or term lungs (Cuna et al , ). Mitoepigenetics such as mitochondrial methylation occur in a variety of cultured mammalian cells, and this process is modulated by DNA methyltransferase 1 in mitochondria (Shock et al , ).…”

Can We Prevent Bronchopulmonary Dysplasia?

“…2 For instance, a recent study identified multiple genes potentially regulated by DNA methylation during normal alveolar septation in the mouse and human lung, and in BPD. 11 In utero smoke exposure modifies the methylation of specific genes, has been associated with changes in indices of global DNA methylation, and biologic pathways impacted through epigenetic changes by in utero smoke are being identified. 12 Maternal prenatal stress, cortisol, in-utero smoke, particulate exposure, and obesity have been shown to be independently associated with child wheeze, likely through programming mechanisms.…”