CFTR Gene Regulation in Human Pancreatic Duct, Bile Duct and Sweat Gland Epithelial Cells

Epithelial cells at many sites in the body are affected by the inherited disorder cystic fibrosis (CF). The lung was the major focus of research until recently, when effective therapeutics became available for most people with CF. There is now renewed interest in CF aetiology in other locations in the body, where the regulatory mechanisms for the CF transmembrane conductance regulator (CFTR) gene are less well-characterised. The definition of the genomic elements controlling CFTR expression and their associated transcription factors is important for the design of gene-based therapies. Here we identify the cis-regulatory elements (CREs) associated with the CFTR locus by open chromatin mapping in pancreatic adenocarcinoma cell lines, primary human pancreatic and bile duct (cholangiocyte) organoids and single cells from tissues, as well as sweat gland coil and duct epithelial cells. We show that broadly these cell types use a combination of CREs that were characterised previously either in airway or intestinal epithelial cells, though not occurring together in these two cell lineages. Moreover, the chromatin structure of the CFTR locus in pancreatic cell lines is consistent with earlier models. We also use bioinformatic tools to predict the transcription factor network in these rare cell lineages from open chromatin peaks genome-wide.