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An EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury.

Published version
Peer-reviewed

Type

Article

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Authors

Hill, Matthew A 
Kollak, Ines 
Keck, Martina 
Schroeder, Victoria 

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.

Description

Keywords

EZH2, TAK1, fibrosis, lung epithelial injury, nuclear actin, Animals, Enhancer of Zeste Homolog 2 Protein, Fibrosis, Histones, Mice, Phosphorylation, Polycomb Repressive Complex 2

Journal Title

EMBO Reports

Conference Name

Journal ISSN

1469-221X
1469-3178

Volume Title

22

Publisher

Wiley