A comprehensive multi-omics and functional study of evolutionary adaptive responses to smoke

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Genomics

Background:

• Cigarette smoking is a major cause of preventable death globally.
• Inhaled smoke damages lung epithelium, contributing to chronic lung diseases.
• Understanding the molecular impact of smoking on the lungs is crucial.

Purpose of the Study:

• To identify the molecular
• smoking signature
• in the lungs of smokers.
• To pinpoint the specific airway epithelial cells affected by smoke.
• To investigate evolutionary adaptations in smoke response genes and identify key regulatory pathways.

Main Methods:

• Transcriptomic analysis across multiple human cohorts.
• Single-cell and spatial transcriptomics to map the smoking signature.
• Comparative genomics between human and non-human primate lungs.
• Methylation and ChIP-seq analyses to identify master regulators.
• Gene knockout studies (NQO1, ALDH3A1) to assess protective functions.

Main Results:

• The
• smoking signature
• was identified, highlighting transcriptomic differences between smokers and non-smokers.
• The surface layer of the airway epithelium was identified as the most affected region.
• A set of human-specific smoke-response genes suggests evolutionary adaptation.
• NRF2 and AhR were identified as master regulators of the smoking signature.
• Knockout of NQO1 and ALDH3A1 demonstrated their protective roles in airway response to smoke.

Conclusions:

• The study defines the molecular landscape of smoking-induced lung damage.
• Airway epithelial surface cells are particularly vulnerable to smoke exposure.
• Human lungs exhibit unique genetic adaptations to smoke.
• NRF2 and AhR are key regulators, and NQO1/ALDH3A1 play protective roles, offering potential therapeutic targets for smoking-related lung diseases.