DNA methylation changes in cystic fibrosis: Cause or consequence?

Twin and sibling studies have shown that lung disease severity is variable among cystic fibrosis (CF) patients and affected to the same extent by genetic and nonheritable factors. Genetic factors have been thoroughly assessed, whereas the molecular mechanisms whereby nonheritable factors contribute to the phenotypic variability of CF patients are still unknown. Epigenetic modifications may represent the missing link between nonheritable factors and phenotypic variation in CF. Herein, we review recent studies showing that DNA methylation is altered in CF and we address three possible factors responsible for these variations: (i) overproduction of reactive oxygen species, (ii) depletion of DNA methylation cofactors and (iii) susceptibility to acute and chronic bacterial infections. Also, we hypothesize that the unique DNA methylation profile of each patient can modulate the phenotype and discuss the interest of implementing integrated genomic, epigenomic and transcriptomic studies to further understand the clinical diversity of CF patients (Graphical Abstract).