Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional (3D) structure and cis-regulatory elements governing the dynamic expression of CFTR need to be considered. In this review, we focus on the higher order chromatin organization required for normal CFTR locus function, together with the complex mechanisms controlling expression of the gene in different cell types impaired by CF pathology. Across all cells, the CFTR locus is organized into an invariant topologically associated domain (TAD) established by the architectural proteins CCCTC-binding factor (CTCF) and cohesin complex. Additional insulator elements within the TAD also recruit these factors. Although the CFTR promoter is required for basal levels of expression, cis-regulatory elements (CREs) in intergenic and intronic regions are crucial for cell-specific and temporal coordination of CFTR transcription. These CREs are recruited to the promoter through chromatin looping mechanisms and enhance cell-type-specific expression. These features of the CFTR locus should be considered when designing gene-editing approaches, since failure to recognize their importance may disrupt gene expression and reduce the efficacy of therapies.
Highlights
The cystic fibrosis transmembrane conductance regulator (CFTR) gene was one of the first genes that was shown to be regulated by elements outside its promoter [1,2,3,4]
CFTR is expressed in many different cell types, both epithelial and non-epithelial, this review will focus on the regulatory mechanisms controlling expression of the gene in epithelial cells as they are best studied
We discuss both older seminal data and more recent advances that define the chromatin architecture of the CFTR locus, reveal multiple cell-type selective cis-regulatory elements within and adjacent to the locus, and identify key activating and repressive transcription factors (TFs)
Summary
The cystic fibrosis transmembrane conductance regulator (CFTR) gene was one of the first genes that was shown to be regulated by elements outside its promoter [1,2,3,4]. CFTR is expressed in many different cell types, both epithelial and non-epithelial, this review will focus on the regulatory mechanisms controlling expression of the gene in epithelial cells as they are best studied We discuss both older seminal data and more recent advances that define the chromatin architecture of the CFTR locus, reveal multiple cell-type selective cis-regulatory elements within and adjacent to the locus, and identify key activating and repressive transcription factors (TFs). These data have renewed importance at a time when gene editing and replacement are being considered among novel therapeutic approaches for CF. CFTR is regulated by post-transcriptional mechanisms including microRNAs, some of which directly target sequences in the 30 untranslated region (UTR) of the gene, these will not be considered further here as they are reviewed elsewhere [14]
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