Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis
| Autor: | Corinne E. Hennessy, Einat I. Rabinovich, David A. Schwartz, Mandal K. Singh, Mick Correll, Naftali Kaminski, Brenda Juan Guardela, Elissa Murphy, Mark W. Geraci, John Tedrow, John Quackenbush, Avrum Spira, Yingze Zhang, Elizabeth J. Davidson, Brent S. Pedersen, Ivana V. Yang, Marvin I. Schwarz, Frank C. Sciurba |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pulmonary and Respiratory Medicine
Genetic Markers Male Quantitative Trait Loci Gene Expression Biology Critical Care and Intensive Care Medicine Epigenesis Genetic Idiopathic pulmonary fibrosis Adrenal Cortex Hormones Pulmonary fibrosis Gene expression medicine Humans Epigenetics Gene Genetics Smoking Methylation respiratory system DNA Methylation Middle Aged medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases Differentially methylated regions Case-Control Studies DNA methylation Cancer research Original Article Female Transcriptome Immunosuppressive Agents |
| Zdroj: | American journal of respiratory and critical care medicine. 190(11) |
| ISSN: | 1535-4970 |
| Popis: | 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 (P2.2 × 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 (P2.2 × 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|