The proteostatic network chaperome is downregulated in F508del homozygote cystic fibrosis

Background: CF patients demonstrate clinical heterogeneity and much remains unknown about how to risk stratify individuals for disease progression. The most common cystic fibrosis mutation, F508del, is a protein folding mutation that has been shown in vitro to negatively affect proteostasis and CFTR transcription. Since CFTR is expressed in the nasal epithelium, we hypothesized that by using unbiased transcriptomics we could gain clinically relevant insights about differential gene expression and heterogeneity in CF patients as well as assess proteostatic dysfunction in the nasal epithelium. Methods: Using nasal curettage and RNA-seq we assessed differential gene expression in F508del homozygotes compared to healthy volunteers. Gene set enrichment analysis was performed using a list of known chaperones. Pilot and validation cohorts were studied. Results: PCA analysis and gene expression heatmaps exhibited greater heterogeneity among CF than healthy volunteers. Differentially expressed genes were enriched for the downregulation of ciliary/microtubular genes and the upregulation of inflammatory/immune response genes in F508del homozygotes compared to healthy volunteers. Gene set analysis identified negative enrichment for chaperone genes and decreased CFTR transcription in the F508del homozygotes. We also found preliminary evidence for the recently identified ionocyte in the nasal specimens. Conclusion: CF patients homozygous for F508del demonstrate heterogeneous gene expression profiles, proteostatic dysregulation, and reduced CFTR transcription. Larger studies are needed to determine whether nasal epithelial gene transcription profiles can be leveraged for insights into disease heterogeneity.