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

Lookup NU author(s): Dr James Garnett

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2021 Boehringer Ingelheim Pharma GmbH & Co. KG. Published under the terms of the CC BY NC ND 4.0 license.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.


Publication metadata

Author(s): Le HQ, Hill MA, Kollak I, Keck M, Schroeder V, Wirth J, Skronska-Wasek W, Schruf E, Strobel B, Stahl H, Herrmann FE, Campos AR, Li J, Quast K, Knebel D, Viollet C, Thomas MJ, Lamb D, Garnett JP

Publication type: Article

Publication status: Published

Journal: EMBO Reports

Year: 2021

Pages: epub ahead of print

Online publication date: 05/07/2021

Acceptance date: 10/06/2021

Date deposited: 19/07/2021

ISSN (print): 1469-221X

ISSN (electronic): 1469-3178

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.15252/embr.202152785

DOI: 10.15252/embr.202152785


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