An EZH2‐dependent transcriptional complex promotes aberrant epithelial remodelling after injury

Abstract

Unveiling the molecular mechanisms of tissue remodelling following injury is imperative to elucidate its regenerative capacity and aberrant repair in disease. Using different omics approaches, we identified enhancer of zester homolog 2 (EZH2) as a key regulator of fibrosis in injured lung epithelium. Epithelial injury drives an enrichment of nuclear transforming growth factor‐β‐activated kinase 1 (TAK1) that mediates EZH2 phosphorylation to facilitate its liberation from polycomb repressive complex 2 (PRC2). This process results in the establishment of a transcriptional complex of EZH2, RNA‐polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial repair programmes. The liberation of EZH2 from PRC2 is accompanied by an EZH2‐EZH1 switch to preserve H3K27me3 deposition at non‐target genes. Loss of epithelial TAK1, EZH2 or blocking nuclear actin influx attenuates the fibrotic cascade and restores respiratory homeostasis. Accordingly, EZH2 inhibition significantly improves outcomes in a pulmonary fibrosis mouse model. Our results reveal an important non‐canonical function of EZH2, paving the way for new therapeutic interventions in fibrotic lung diseases.

Time and phenotype-dependent transcriptome analysis in AAV-TGFβ1 and Bleomycin-induced lung fibrosis models

“…In this context, AAV’s low immunogenicity in mice is an important property, as it allows for specific modulation of pathways without interference by vector-targeted immune responses. Since its development, the AAV-TGFβ1 model has been frequently used to study drug candidates and explore target function in our group 68 – 70 . Further technological refinement of the model might be achieved in the future by using self-complementary AAV vectors, which lead to a faster onset of transgene expression 71 .…”

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate

“…Our finding that Ezh2 null organoids have a significant loss in a Krt5 − /Krt17 + /Krt8 + /Fn1 + cell population suggests that Ezh2 expression may be a key contributor to the pathology of pulmonary fibrosis. A recent paper showed that inhibition of EZH2 by the inhibitor, GSK126, was able to abrogate transforming growth factor β-induced lung fibrosis phenotypes, and our organoid model presents additional mechanistic insight into this phenomenon ( Le et al., 2021 ). The increased expression of AT2 marker Lamp3 and the alveolar developmental marker Foxp2 suggests that loss of Ezh2 expression leads to accumulation of BASC/AT2 progenitor cells that may be unable to transition into the KRT8 + state, or further into AT1 cells.…”

Elucidating shared biomarkers in gastroesophageal reflux disease and idiopathic pulmonary fibrosis: insights into novel therapeutic targets and the role of angelicae sinensis radix

“…It plays an essential role in both IPF and GERD. The POLR2 plays a crucial role in the abnormal repair of respiratory epithelial cells ( Le et al, 2021 ). It also develops esophageal acidic microenvironment pH by binding to eotaxin-3 protein, an essential target of eosinophilic esophagitis ( Zhang et al, 2012 ).…”