Introduction

COPD is a progressive airway disease triggered by lifetime cigarette smoke exposure. Female smokers are 50% more likely to develop COPD and experience worse exacerbations than males. Epigenetic changes affect COPD. H3K27 is a histone mark demethylated by UTX and UTY; only males express UTY. Altered methylation of H3K27 is associated with COPD status. Differences in function between UTX and UTY may contribute to sex differences in COPD. We aimed to explore the expression of UTX and UTY in COPD and how these genes regulate cellular processes.

Methods

UTX and UTY gene expression was correlated with lung function (FEV1/FVC) in COPD patients and stratified by sex. Single and double knockouts (DKO) were created for UTX and UTY. Regulation of cell death after 24hr cigarette smoke exposure (CSE) in KO cell lines was assessed, and proliferation rates were measured after 96hr. RNA-sequencing (RNA-seq) explored pathways contributing to observed changes in cell death and proliferation.

Results

UTY positively correlated with lung function in male COPD patients, adjusting for age and smoking history (p<0.05). UTX showed no significant relationship. UTY KOs and DKOs showed increased survival to CSE, compared to wildtype (p<0.05). Only DKO cells had reduced cell proliferation (p<0.05). RNA-seq revealed mitochondrial and histidine metabolism are altered in UTY KO and DKO cells. We identify a novel regulatory axis that may regulate cigarette smoke-induced cell death.

Conclusion

All altered responses in single KO cells are exacerbated in double knockout cells, indicating overlapping functions for UTX and UTY. Although, some differences exist. This difference may contribute to sex differences in COPD development and disease progression.