Epigenetic regulation and chromatin organization in cystic fibrosis airways

Cystic fibrosis (CF) is caused by pathogenic variants of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF in the airways is associated with dehydrated and hyperconcentrated mucus, impaired mucociliary transport, and inflammation. Although CF is a genetic disorder, CFTR sequence variations alone may not fully explain its phenotypic variation. Additionally, while pharmacological CFTR modulators that correct CFTR protein function greatly improve clinical outcomes, people with CF treated with modulators can still exhibit abnormal mucus and persistent inflammation compared to non-CF individuals. As such, understanding the regulation of mucus and inflammation remains crucial to full characterization and management of CF. We suggest that non-DNA-sequence-based mechanisms that regulate CFTR, mucus, and inflammation contribute to CF pathogenesis. This review highlights three features of transcriptional regulation known to modify gene expression (DNA methylation, histone modifications, and three-dimensional chromatin organization) and their role in CF airways. For each feature, we discuss current knowledge of their role in regulating CFTR, gel-forming mucin genes, and inflammation in CF contexts. We also highlight exploratory efforts to target epigenetic mechanisms as CF treatment strategies and suggest that epigenetics and chromatin organization offer a rich space for future CF research.