DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Clinical Epigenetics Année : 2016

DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis

Résumé

Background 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. Results We 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. Conclusions DNA 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.
Fichier principal
Vignette du fichier
13148_2016_Article_300.pdf (2.19 Mo) Télécharger le fichier
13148_2016_300_MOESM2_ESM.pdf (212.18 Ko) Télécharger le fichier
Origine : Publication financée par une institution
Origine : Publication financée par une institution

Dates et versions

inserm-01467873 , version 1 (14-02-2017)

Identifiants

Citer

Milena Magalhães, Isabelle Rivals, Mireille Claustres, Jessica Varilh, Mélodie Thomasset, et al.. DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis. Clinical Epigenetics, 2016, 9 (1), pp.19. ⟨10.1186/s13148-016-0300-8⟩. ⟨inserm-01467873⟩
263 Consultations
441 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More