An EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury.
Huy Q LeMatthew A HillInes KollakMartina KeckVictoria SchroederJohannes WirthWioletta Skronska-WasekEva SchrufBenjamin StrobelHeiko StahlFranziska E HerrmannAlexandre R CamposJun LiKarsten QuastDagmar KnebelCoralie ViolletMatthew J ThomasDavid LambJames P GarnettPublished in: EMBO reports (2021)
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.
Keyphrases
- long noncoding rna
- long non coding rna
- transforming growth factor
- transcription factor
- stem cells
- gene expression
- systemic sclerosis
- mesenchymal stem cells
- oxidative stress
- pulmonary fibrosis
- single cell
- metabolic syndrome
- protein kinase
- dna methylation
- skeletal muscle
- tyrosine kinase
- heat shock protein
- respiratory tract
- bone marrow
- cell migration