A number of faculty members at UAB are engaged in investigating the pathogenesis and treatments for idiopathic pulmonary fibrosis (IPF). A recent publication by Dr. Yan Sanders, et al in the American Journal of Respiratory and Critical Care Medicine highlights the importance of epigenetic mechanisms involving DNA methylation in IPF.
DNA methylation can affect gene expression profiles in response to environmental stimuli and in aging. This is the first study to apply a whole genome approach to DNA methylation in IPF patients. Dr. Sanders and colleagues compared DNA methylation and RNA gene expression profiles in lung tissue from 12 IPF patients and 7 control patients. They found that overall DNA methylation status did not differ in the two patient populations, but IPF patients did have increased expression of de novo DNA methyltransferases, especially in the hyperplastic alveolar epithelium adjacent to fibroblastic foci. They were also able to identify 16 genes for which there were inverse relationships between DNA methylation status and gene expression. They validated 4 genes known to be important in fibrosis, CLDN5, ZNF467, TP53INP1, and DDAH1.
This work provides new insights into differences in gene regulation and gene expression patterns in patients with IPF. The methods used in this paper can be expanded in the future to help identify biomarkers for progression of disease, understand the etiology and pathogenesis of the disease, and discover new target pathways for therapeutics for this devastating disease.
Altered DNA Methylation Profile in Idiopathic Pulmonary Fibrosis.
Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK, Bray M, Zhang K, Thannickal VJ, Hagood JS.
Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States.
Rationale: DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).
Objective: To determine the DNA methylation changes in IPF and their effects on gene expression.
Methods: Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome wide DNA methylation and RNA expression using DNA hybridization to Illumina Human Methylation27 BeadChips and RNA hybridization to Illumina Human HT-12 BeadChips. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.
Measurements and Main Results: DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hyper-methylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.
CONCLUSIONS: Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
PMID: 22700861 [PubMed - as supplied by publisher]