Epigenetic marks are likely to explain variability of response to antigen in granulomatous lung disease.
To identify DNA methylation and gene expression changes associated with chronic beryllium disease (CBD) and sarcoidosis in lung cells obtained by bronchoalveolar lavage (BAL).
BAL cells from CBD (n=8), BeS (n=8), sarcoidosis (n=8), and additional progressive (n=9) and remitting (n=15) cases of sarcoidosis were profiled on the Illumina 450K methylation and Affymetrix/Agilent gene expression microarrays. Statistical analyses were performed to identify DNA methylation and gene expression changes associated with CBD, sarcoidosis, and disease progression in sarcoidosis. DNA methylation array findings were validated by pyrosequencing.
We identified 52,860 significant (p<0.005 and q<0.05) CpGs associated with CBD; 2,726 CpGs near 1,944 unique genes have >25% methylation change. 69% of differentially methylated genes are significantly (q<0.05) differentially expressed in CBD, with many canonical inverse relationships of methylation and expression in genes critical to Th1 cell differentiation, chemokines and their receptors, and other genes involved in immunity. Testing of these CBD-associated CpGs in sarcoidosis reveals that methylation changes approach significance (q<0.15) and are methylated in the same direction, suggesting similarities between the two diseases with more heterogeneity in sarcoidosis. Analysis of progressive vs remitting sarcoidosis identified 15,215 CpGs (p<0.005 and q<0.05) but only 801 of them have >5% methylation change, demonstrating that DNA methylation marks of disease progression changes are more subtle.
Our study highlights the significance of epigenetic marks in lung immune response in granulomatous lung disease.