Characterization of the cystic fibrosis transmembrane conductance regulator promoter region. Chromatin context and tissue-specificity.

Expression of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) is tightly regulated. Using a panel of cell lines expressing different levels of CFTR mRNA, we investigated the mechanisms mediating control of CFTR transcription. In highly expressing cells, multiple sites of transcription initiation can be identified between positions -95 and +50 of the CFTR gene, and an alternatively initiated splice variant transcript is also present. Nonepithelial cell lines expressing very low levels of CFTR utilize a start site at -32. Promoter sequence elements from -83 to +111 are at least partially responsible for dictating CFTR transcriptional tissue-specificity, while multiple elements located farther 5' augment promoter strength. Analysis of the chromatin structure and methylation status of the CFTR promoter region reveals cell line differences which correlate with expression levels, suggesting that the physical context of the CFTR gene in vivo may contribute significantly to appropriate regulation of CFTR transcription. Taken together, these findings indicate that cellular control of CFTR gene expression is likely to be a complex function of several overlapping regulatory pathways.