DNA polymorphisms in potential regulatory elements of the CFTR gene alter transcription factor binding

Over one thousand mutations have been identified to date in the cystic fibrosis transmembrane conductance regulator gene (CFTR); however, about 5–10% of mutations remain undefined. It is likely that some of these undefined mutations occur within regulatory elements for the CFTR gene. Tissue-specific regulatory elements for CFTR are located outside the basal promoter region and may be associated with DNase I hypersensitive sites (DHS). We previously described a DHS at +15.6 kb 3′ to the CFTR gene, which showed tissue specificity in vivo and was evaluated as a candidate regulatory element for CFTR. Polymorphisms in regulatory elements may have a significant effect on their activity and hence on the levels of gene expression. Two C→T polymorphisms were identified within the +15.6 kb region that occurred on both cystic fibrosis (CF) and non-CF alleles. Both of the polymorphisms altered DNA-protein binding, as shown by electrophoretic mobility shift assays (EMSA). These changes in transcription factor binding at a putative regulatory region could influence CFTR gene expression.