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

Cigarette smoking remains one of the leading causes of preventable death worldwide. Upon inhalation, smoke induces damage to the lung epithelium, which can be the driving force for the development of chronic lung diseases. In the current study, we identified the "smoking signature" by assessing transcriptomic differences between current and non-smokers in multiple cohorts. By mapping the smoking signature onto single-cell and spatial transcriptomics data, we identified the surface layer of the airway epithelium as the part of the airways most affected by smoke. Next, by comparing the smoking signature between lungs of humans and non-human primates, we identified a cluster of human-specific smoke-response genes, suggesting an evolutionary adaptation to smoke exposure. Methylation and ChIP-seq analyses were used to identify NRF2 and AhR as master regulators of the smoking signature. Knockout of smoking signature-genes NQO1 and ALDH3A1 revealed their role in protective responses of the airways upon smoke exposure.