Wednesday, January 15, 2025
1/15/2025
Project Summary: Influenza is a major global health threat causing over half a million deaths each year. Certain virulent strains, such as H1N1, can cause extensive lung damage, leading to dysplastic repair and the formation of Krt5+ basal cell pods in the damaged alveolar. Despite their temporary barrier restoration capabilities, these basal cells fall short in facilitating full tissue repair, resulting in the accumulation of dysplastic tissue and compromised lung function. The abnormal repair process mirrors patterns seen in chronic lung diseases like idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), accentuating the urgency to understand the cellular and molecular mechanisms governing lung remodeling and repair. Using mouse models exposed to the influenza A virus strain PR8, we and others have demonstrated that these nascent basal cells predominantly originate from a rare subset of migratory airway cells. Furthermore, we found that Enhancer of Zeste 2 (Ezh2) is marked upregulated in the hyperplastic basal cells post-PR8 infection. Conventionally, Ezh2, as the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), has been recognized for its ability to repress gene expression via the trimethylation of lysine 27 on histone 3 (H3K27me3). However, these basal cells post-PR8 infection showed lower H3K27me3 levels compared to nearby cell types, aligning with low expression of other PRC2 components like Eed. This implies a potential PRC2-independent function for Ezh2 in controlling basal cell hyperplasticity. Additionally, Ezh2 deletion in airway epithelial progenitor cells led to marked reduction Krt5+ pod after PR8 infection. Moreover, we also observed a significant upregulation of Sox9 in the hyperplastic basal cells post-PR8 infection. Sox9 deletion also led to reduction of the Krt5+ pod area mirroring Ezh2 deletion phenotype after PR8 infection. Furthermore, inhibition of Ezh2 resulted in suppressed Sox9 expression in basal cells both in vivo and in vitro, suggested Ezh2 may serve as a transcription activator for Sox9. Based on these data, our central hypothesis is that Ezh2 functions in a PRC2-independent manner to regulate basal cell dynamics post-PR8 infection. In Aim 1, we will investigate whether the phosphorylation-mediated non-canonical role of Ezh2 plays a regulatory function in basal cell dynamics following PR8 infection. In Aim2, we will identify the unique gene targets of non-canonical Ezh2 and ascertain whether Sox9 serves as an integral downstream effector in basal cells post-PR8 infection. In Aim3, discern the interacting partners external to the PRC2 complex with which Ezh2 associates to exert its non-canonical role in basal cells post-PR8 infection. Additionally, we seek to identify the factors that initiate these interactions and changes. Completion of these aims will provide transformative insights into the mechanisms underpinning lung tissue remodeling post-influenza and the broader implications for pulmonary medicine.
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