MassIVE MSV000087321

Partial Public PXD025677

EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury

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Description

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 that initiates a fibrotic cascade in injured lung epithelium. Epithelial-injury-driven enrichment of nuclear transforming growth factor-b-activated kinase 1 (TAK1) mediates EZH2 phosphorylation to facilitate the release of EZH2 from polycomb repressive complex 2 (PRC2). This process leads to the establishment of a fibrotic transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial lung repair programs. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve silencing 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. [doi:10.25345/C5PZ3H] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Actin ; EZH2 ; Lung fibrosis ; RNA-polymerase II

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Principal Investigators:
(in alphabetical order) 		James Peter Garnett, Boehringer Ingelheim Pharma GmbH, Germany
Submitting User: alexcampos
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