American Thoracic Society, American Journal of Respiratory and Critical Care Medicine, 11(190), p. 1263-1272
DOI: 10.1164/rccm.201408-1452oc
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Rationale: IPF is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome. Objectives: To identify methylation marks that modify gene expression in IPF lung. Methods: We assessed DNA methylation (CHARM arrays) and gene expression (Agilent gene expression arrays) in 94 IPF and 67 control subjects and performed integrative genomic analyses to define methylation-gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper) and performed functional validation of one of the genes identified by our analysis. Measurements and Main Results: We identified 2130 differentially methylated regions (<5% false discovery rate, FDR) of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (p<2.2 x 10-16). We validated 13/15 DMRs by targeted analysis of methylation. Methyl-eQTL identified methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (p<2.2 x 10-16). We found five trans methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (CASZ1, FOXC1, MXD4, and ZDHHC4). We studied the in vitro effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL. Conclusions: These results suggest that DNA methylation may be involved in the pathogenesis of IPF.