Single-cell RNA-sequencing co-expression analysis with CFTR and CF modifier genes in lung tissue.

Area of Science:

• Pulmonary Medicine
• Genetics
• Molecular Biology

Background:

• Cystic fibrosis (CF) is primarily caused by loss-of-function variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.
• Other modifier genes influence CF disease severity, suggesting a cooperative relationship with CFTR in normal tissues.
• Understanding these interactions is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the co-expression relationships between CFTR and modifier genes in lung cells.
• To identify specific cell types involved in the cystic fibrosis lung phenotype.
• To support the prioritization of therapeutic targets for cystic fibrosis.

Main Methods:

• Utilized SmartSeq2 single-cell RNA sequencing data from non-CF lung tissue to analyze CFTR and modifier gene co-expression.
• Employed a zero-inflated negative binomial model to statistically assess co-expression associations.
• Confirmed findings using 10X Chromium single-cell RNA sequencing data from both CF and non-CF lung studies.

Main Results:

• Differentiating basal, club, and alveolar epithelial type 2 cells showed high CFTR expression and numerous significant co-expression relationships with modifier genes.
• A significant co-expression trio involving CFTR, SLC6A14, and SLC26A9 was identified in alveolar epithelial type 2 cells (p < 0.05).
• Alveolar epithelial type 2 cells demonstrated strong co-expression with two key cystic fibrosis modifier genes.

Conclusions:

• CFTR-modifier gene co-expression indicates coordinated expression in basal, club, and alveolar epithelial type 2 cells.
• Alveolar epithelial type 2 cells are a key cell type exhibiting strong co-expression with established cystic fibrosis modifiers.
• These findings highlight potential therapeutic targets within specific lung cell populations for cystic fibrosis treatment.