Investigating genetic and molecular factors contributing to sexual dimorphism in lung disease
- Publication Type:
- Thesis
- Issue Date:
- 2023
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Differences in disease susceptibility, progression and severity patterns exist between males and females. Asthma and chronic obstructive pulmonary disease (COPD) are pervasive respiratory diseases that demonstrate sexual dimorphism. Male children experience increased asthma rates and worse health outcomes than female children, with this trend reversing after puberty. Importantly, sex differences exist for the hallmark features of asthma and COPD in inflammation, airway fibrosis and remodelling, and regulation of cell death. Despite a clear relationship between biological sex and disease, the contributory genetic and molecular factors remain poorly understood. Preliminary analysis of patient-derived primary airway cells identified that female-derived cells produce increased levels of the proinflammatory cytokine IL6 compared to male cells, irrespective of disease diagnosis. Therefore, sex differences in immunoregulation are observable ex vivo, where biological factors such as sex hormones are removed. Thus, intrinsic molecular and genetic factors such as the sex chromosomes likely contribute to this difference.
Highly similar but non-exact gene homologs on the X and Y chromosomes demonstrate imbalanced expression. Females express double the X-chromosome-linked homolog, whilst only males express the Y-chromosome-linked version. This imbalanced expression or function of X and Y chromosome homologs may contribute to sex differences in inflammatory, fibrotic and cell death-related processes. We aimed to explore, characterise and compare the function of the ZFX/ZFY, RPS4Y1/RPS4X and UTX/UTY gene pairs that have vital genome regulatory functions. This includes mediating gene transcription, protein translation and histone demethylation. As such, they may specifically regulate pathological processes between males and females.
CRISPR-Cas9 knockout cell lines were generated for each candidate gene in male-derived A549 cells. Disease-relevant phenotypes were analysed in knockout cells, such as immunoregulation, cell proliferation, cell adhesion, cell death and extracellular matrix protein production. RNA-sequencing and proteomics analyses were paired with independent patient cohorts to identify pathways regulated by the candidate genes and highlight whether they contribute to clinically relevant outcomes, such as lung function measurements.
For the first time, we show novel differences in the function of the XY gene pairs that directly relate to the hallmark disease features of inflammation, fibrosis and cell death. These divergent functions may contribute to sex differences in the susceptibility and severity of asthma and COPD. We relate gene pathways regulated by the candidate genes to clinical measurements. This vital data provides a foundation for identifying target pathways for the development of new, more effective treatments to improve patient outcomes.
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