Relationship of DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis

• Published in: American journal of respiratory and critical care medicine Vol. 190; no. 11; pp. 1263 - 1272
• Main Authors: Yang, Ivana V., Pedersen, Brent S., Rabinovich, Einat, Hennessy, Corinne E., Davidson, Elizabeth J., Murphy, Elissa, Guardela, Brenda Juan, Tedrow, John R., Zhang, Yingze, Singh, Mandal K., Correll, Mick, Schwarz, Marvin I., Geraci, Mark, Sciurba, Frank C., Quackenbush, John, Spira, Avrum, Kaminski, Naftali, Schwartz, David A.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2014
• Subjects: Adrenal Cortex Hormones - therapeutic use; Arrays; Cancer; Case-Control Studies; Consortia; Data analysis; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - physiology; Epigenetics; Female; Gene Expression; Genetic Markers; Genomes; Humans; Idiopathic Pulmonary Fibrosis - genetics; Immunosuppressive Agents - therapeutic use; Lung diseases; Male; Middle Aged; Original; Pathogenesis; Pulmonary fibrosis; Quality control; Quantitative Trait Loci - genetics; Smoking - epidemiology; Smooth muscle; Transcriptome - genetics; DNA methylation; mapping; quantitative trait; gene expression; pulmonary fibrosis
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201408-1452OC

Idiopathic pulmonary fibrosis (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. To identify methylation marks that modify gene expression in IPF lung. We assessed DNA methylation (comprehensive high-throughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with 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. We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (P < 2.2 × 10(-16)). We validated 13/15 DMRs by targeted analysis of methylation. Methylation-expression quantitative trait loci (methyl-eQTL) identified methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (P < 2.2 × 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 (castor zinc finger 1 [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. These results suggest that DNA methylation may be involved in the pathogenesis of IPF.