title: Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To identify methylation marks that modify gene expression in IPF lung.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These results suggest that DNA methylation may be involved in the pathogenesis of IPF.
authors.affiliation: 1 Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.forename: Brent S
authors.initials: BS
authors.lastname: Pedersen
authors.forename: Einat
authors.initials: E
authors.lastname: Rabinovich
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Hennessy
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Davidson
authors.forename: Elissa
authors.initials: E
authors.lastname: Murphy
authors.forename: Brenda Juan
authors.initials: BJ
authors.lastname: Guardela
authors.forename: John R
authors.initials: JR
authors.lastname: Tedrow
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mandal K
authors.initials: MK
authors.lastname: Singh
authors.forename: Mick
authors.initials: M
authors.lastname: Correll
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.forename: Mark
authors.initials: M
authors.lastname: Geraci
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology; D059467:Transcriptome / Q000235:genetics*
chemical_list: D000305:Adrenal Cortex Hormones; D005819:Genetic Markers; D007166:Immunosuppressive Agents
keywords: DNA methylation; gene expression; mapping; pulmonary fibrosis; quantitative trait