Abstract
BackgroundIdiopathic 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.MethodsWe 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).ResultsOur 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 (R2 = 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.ConclusionOur 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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course
The receiver operator characteristic (ROC) curves for each nucleosome assay in the untreated IPF group vs healthy subjects (HS) were established
The area under the curve (AUC) for the ROC curve computed by this logistic regression was 0.93 (p < 0.001) with 91% sensitivity at 80% specificity for the discrimination of IPF patients vs HS (Fig. 2)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course. Guiot et al Clinical Epigenetics (2017) 9:84 exposure effects in genetically predisposed individuals and may lead to the transcriptional changes that occur in IPF [8]. Nucleosomes are the basic unit of chromatin consisting in a 147-bp DNA strand wrapped around a core of eight histone protein cores. During cellular damage such as apoptosis or necrosis, chromatin is fragmented into oligo- or mono-nucleosomes which are released into the blood stream [11, 12]. Epigenetic nucleosome modifications including histone acetylation, histone methylation, or DNA methylation play fundamental roles in gene regulation and expression [14]. As a new approach for diagnosis and monitoring of IPF, we have studied the relevance of some nucleosome epigenetic features including histone and DNA modifications as well as histone variants or nucleosome adducts in serum samples of treated and untreated IPF patients
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