Abstract
BackgroundLung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients.ResultsWe profiled DNA methylation at CFTR, the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ≥18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific trans-factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity: HMOX1 and GSTM3 in nasal epithelial samples; HMOX1 and EDNRA in blood samples. The association between pulmonary severity and DNA methylation at EDNRA was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at GSTM3 were associated with the GSTM3*B allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis.ConclusionsDNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of CFTR and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity.
Highlights
Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure
This is quite high because the standard deviation of the methylation around its mean value was of the order of 0.43 in blood and of 0.52 in nasal epithelial cells (NEC) samples, for both the CF patients and the healthy controls
Using the mean DNA methylation in the region, we found that HMOX1 was differentially methylated in NEC samples (Student p = 0.018) and blood cell samples (Wilcoxon p = 0.009) of CF patients compared with controls, but the direction of the methylation change was not the same in the two tissue models (Fig. 4a, b)
Summary
Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients. Lung disease progression is variable among CF patients and depends on the combination of three factors: (i) DNA mutations in the CFTR gene, (ii) polymorphic variations in other genes, and (iii) environmental exposure. We hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation changes at CF modifier genes contribute to the lung function variations observed in CF patients. Three genes (ATF1, DUOX2, and YY1) were differentially expressed in nasal epithelial cells collected from CF patients characterized by extreme disease phenotypes [5]
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