Altered epigenetic features in circulating nucleosomes in idiopathic pulmonary fibrosis

• Main Authors: J. Guiot, I. Struman, V. Chavez, M. Henket, M. Herzog, K. Scoubeau, N. Hardat, B. Bondue, JL. Corhay, C. Moermans, R. Louis
• Format: Article
• Language: English
• Published: BMC 2017-08-01
• Series: Clinical Epigenetics
• Subjects: Idiopathic pulmonary fibrosis; Epigenetic; Biomarkers; Nucleosome modifications; Interstitial lung disease
• Online Access: http://link.springer.com/article/10.1186/s13148-017-0383-x

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course. Polymorphisms and environmentally induced epigenetic variations seem to determine individual susceptibility to the development of lung fibrosis. Methods We have studied circulating epitopes on cell-free nucleosomes (cfnucleosomes) in 50 IPF patients. We have compared untreated IPF (n = 23) with IPF receiving antifibrotic therapy (n = 27) and healthy subjects (HS) (n = 27). We analyzed serum levels of five cfnucleosomes including bound HMGB1 (nucleosomes adducted to high-mobility growth protein B1), mH2A1.1 (nucleosomes containing the histone variant mH2A1.1), 5mC (nucleosomes associated with methylated DNA), and H3K9Ac and H3K27Ac (nucleosomes associated with histone H3 acetylated at lysine 9 or 27 residue). Results Our findings showed that serum levels of bound HMGB1, mH2A1.1, 5mC, H3K9Ac, and H3K27Ac were significantly lower in IPF patients than in HS (p < 0.001, p < 0.001, p < 0.01, p < 0.001, and p < 0.0001, respectively). Moreover, we found differences in epigenetic profiles between untreated IPF patients and those receiving anti-fibrotic therapy with mH2A1.1 and 5mC being significantly lower in untreated than in treated patients (p < 0.01 and p < 0.05, respectively). Combination of four cfnucleosomes (HMGB1, 5mC, H3K9Ac, and H3K27Ac) allow to discriminate IPF vs HS with a good coefficient of determination (R 2 = 0.681). The AUC for the ROC curve computed by this logistic regression was 0.93 (p < 0.001) with 91% sensitivity at 80% specificity. Conclusion Our observations showed that cfnucleosomes (bound HMGB1, mH2A1.1, 5mC, H3K9Ac, and H3K27Ac) might have potential as biomarkers for diagnosis and treatment response. These results deserve further validation in longitudinal cohorts.