Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis

Ivana V. Yang, Brent S. Pedersen, Einat Rabinovich, Corinne E. Hennessy, Elizabeth J. Davidson, Elissa Murphy, Brenda Juan Guardela, John R. Tedrow, Yingze Zhang, Mandal K. Singh, Mick Correll, Marvin I. Schwarz, Mark Geraci, Frank C. Sciurba, John Quackenbush, Avrum Spira, Naftali Kaminski, David A. Schwartz

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Rationale: 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. Objectives: To identify methylation marks that modify gene expression in IPF lung. Methods: We assessed DNA methylation (comprehensive highthroughput 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. Measurements and Main Results: We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with signi ficant 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) identifi ed methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (P < 2.2 × 10-16). We found fi ve 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).Westudied 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.

Original languageEnglish (US)
Pages (from-to)1263-1272
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume190
Issue number11
DOIs
StatePublished - Dec 1 2014

Keywords

  • DNA methylation
  • Gene expression
  • Mapping
  • Pulmonary fibrosis
  • Quantitative trait

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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  • Cite this

    Yang, I. V., Pedersen, B. S., Rabinovich, E., Hennessy, C. E., Davidson, E. J., Murphy, E., Guardela, B. J., Tedrow, J. R., Zhang, Y., Singh, M. K., Correll, M., Schwarz, M. I., Geraci, M., Sciurba, F. C., Quackenbush, J., Spira, A., Kaminski, N., & Schwartz, D. A. (2014). Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine, 190(11), 1263-1272. https://doi.org/10.1164/rccm.201408-1452OC