Global DNA Methylation Levels in Lung Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis Compared to Nonfibrotic Controls

ABSTRACT: Fibroblasts are the key effector cells in idiopathic pulmonary fibrosis (IPF), a chronic, progressive scarring disorder that results in impaired gas exchange and respiratory failure. Fibroblasts from IPF patients exhibit aberrant expression of multiple genes, but the DNA methylome of IPF fibroblasts has never been characterized. We utilized the HumanMethylation27 array, which assays the DNA methylation level of 27,568 CpG sites to compare the DNA methylation patterns of IPF fibroblasts (n=6) with those of nonfibrotic patient controls (n=3) and commercially available normal lung fibroblast cell lines (CCL190, CCL204, and CCL210). Multiple CpG sites across the genome were differentially methylated (as defined by P value less than 0.05 and fold change greater than 2) in IPF fibroblasts compared to fibroblasts from nonfibrotic controls. These methylation changes occurred in both genes recognized to be important in fibroproliferation and extracellular matrix generation, as well as in genes not previously recognized to participate in those processes (including organ morphogenesis and potassium ion channels). We used bisulfite sequencing to independently verify DNA methylation changes in 3 genes (CDKN2B, CARD10, and MGMT); these methylation changes corresponded with changes in gene expression at the mRNA and protein level. These changes in DNA methylation were stable throughout multiple cell passages. DNA methylation changes may thus help to explain a proportion of the differences in gene expression previously observed in studies of IPF fibroblasts. Moreover, significant variability in DNA methylation was observed among individual IPF cell lines, suggesting that differences in DNA methylation may contribute to fibroblast heterogeneity among patients with IPF. These results demonstrate that IPF fibroblasts exhibit global differences in DNA methylation that may contribute to the excessive fibroproliferation associated with this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56074 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA242344

REPOSITORIES: GEO