Epigenetic de-repression of basal cell metaplasia in aging AT2 cells is a risk factor for idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a fatal, age-associated lung disease in which alveolar type II (AT2) cells lose regenerative capacity and can adopt aberrant basal-like fates that promote fibrosis. Using 3D organoid co-cultures with primary human fibroblasts, we find that healthy human AT2 cell trans-differentiation into KRT5+/KRT17+ basal cells increases progressively with age, while differentiation into RAGE+ AT1-like cells decreases. We identify a shared gene signature in AT2 cells at downstream targets of p63 characterized both by acquisition of bivalent, poised chromatin marks with age and increased accessibility in IPF, indicating epigenetic "priming" towards a basal cell lineage. In vitro treatment of young AT2 cells with IL-1{beta} recapitulates this priming toward basal differentiation via a NF-kB-regulated histone demethylase, JMJD3. Conversion of primed AT2 cells to a basal fate requires recruitment of a shared transcription factor, KLF5, from AT1-specific to basal-specific promoters by HIF-1. AT2 cells instead convert to KRT5-/KRT17+ basaloid cells via a non-age-dependent pathway that requires KLF5-SMAD2/3 complexing through TGF{beta}1 signaling. These findings define an inflammation-driven epigenetic de-repressive mechanism that links aging, inflammatory stress, hypoxia, and dysfunctional epithelial metaplasia, and accounts for the likely origin of aberrant epithelial cell populations in fibrotic lung disease.