Comparative Single-Cell Transcriptomics Uncovers Shared and Distinct Molecular Signatures in Cystic Fibrosis and...

Area of Science:

• Genomics
• Molecular Biology
• Respiratory Medicine

Background:

• Cystic Fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are inherited respiratory diseases impairing mucociliary clearance.
• Current management for PCD often borrows from CF care, despite distinct underlying genetic and molecular causes.

Purpose of the Study:

• To conduct a comparative transcriptomic analysis between CF and PCD.
• To identify distinct cellular heterogeneity, molecular pathways, and gene networks differentiating CF and PCD.

Main Methods:

• Comparative transcriptomic analysis using public and in-house sequencing data.
• Fine-tuning a pre-trained transformer model (scGPT) for gene regulatory network exploration.
• Differential attention analysis to identify pathway alterations.

Main Results:

• Distinct molecular signatures were identified for PCD and CF compared to healthy cells.
• The NRF2 pathway was significantly overrepresented in PCD ciliated cells.
• Both PCD and CF secretory cells showed increased immune/inflammatory signaling, with CF exhibiting a stronger inflammatory pattern and UPR activation.

Conclusions:

• CF and PCD possess unique molecular profiles that necessitate distinct therapeutic approaches.
• Transcriptomic analysis and AI-driven tools like scGPT can elucidate condition-specific pathways.