Author(s): Anne Bergougnoux aff1 aff2 aff3 , Mireille Claustres aff1 aff2 aff3 , Albertina De Sario [*] aff1 aff2
asthma; bronchoalveolar lavage; chronic obstructive pulmonary disease; cigarette smoking; cystic fibrosis; DNA methylation; nasal epithelial cells; sputum
DNA methylation & airway diseases
In mammals, DNA methylation regulates gene expression and ensures genome stability. Methylation almost exclusively occurs in the context of the CpG dinucleotide, a cytosine followed by a guanosine residue in the same DNA strand. CpG dinucleotides are under-represented, excepted in CpG islands, which are GC-rich, CpG dense, and, on average, 1 kb long DNA sequences [ 1 ]. About 50% of CpG islands colocalize with the promoter of annotated genes; other CpG islands (named 'orphan'), map within intra- and intergenic regions [2,3 ]. Methylated CpG dinucleotides are bound by DNA methyl-CpG binding proteins that recruit co-repressors thus favoring chromatin compaction and gene repression [4 ]. In promoters and other cis -regulatory sequences (i.e., enhancers, insulators), DNA methylation may hamper transcription factor binding, further contributing to gene silencing [ 1 ]. The role of orphan CpG islands is not yet completely elucidated. It has been suggested that they may correspond to unsuspected promoters, mark the transcription start site of regulatory long noncoding RNAs, affect the alternative splicing of genes and downregulate transcriptional elongation [ 1 ]. For a more detailed description of the complex correlation between DNA methylation and gene transcription, the reader is referred to one of the many published reviews [1,4,5 ].
Waves of DNA methylation and demethylation occur in the mammalian genome during embryo and germ cell development as part of a well-orchestrated cellular differentiation program [6 ]. During fetal life and after birth, DNA methylation continues to play a pivotal role in cellular commitment and differentiation [7-10 ]. More than 100 differentially methylated regions (DMRs) are associated with genes important for lineage commitment in regulatory T cells (Tregs) compared with naïve T cells [11 ]. Among them, Foxp3 , which encodes a major regulator of T cell differentiation, is highly methylated in naïve T cells and slightly methylated in Tregs [12 ]. A complex dynamic change of DNA methylation is observed in the IL-4 gene. The 5' region, hypermethylated in naïve T cells, loses methylation in differentiated T helper 2 cells, where the gene is highly expressed. Conversely, the 3' region is hypomethylated in naïve cells and hypermethylated upon T helper 1 differentiation [13 ].
Besides these programmed changes, gain and loss of DNA methylation occur in various genomic regions as a consequence of cellular and environmental stresses and stochastic changes during lifetime. Because the respiratory system is commonly exposed to environmental stimuli (chemicals, dust, bacteria, viruses, etc.), the epigenome of the pulmonary cells is prone to dynamic changes that may, ultimately, affect gene expression. In acute and chronic lung diseases, airway tissues are exposed not only to external pollutants but also to the high cellular stress that is generated by the inflammatory and immune responses. These reiterative stresses may alter the epigenome, thereby impacting the etiology and progression of airway diseases. Intrauterine...