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EZH2 依赖性转录复合物促进损伤后异常上皮重塑。

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

机构信息

Lung Repair & Regeneration Department, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

University of Bath, Bath, UK.

出版信息

EMBO Rep. 2021 Aug 4;22(8):e52785. doi: 10.15252/embr.202152785. Epub 2021 Jul 5.

DOI:10.15252/embr.202152785
PMID:34224201
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8339687/
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.

摘要

揭示损伤后组织重塑的分子机制对于阐明其在疾病中的再生能力和异常修复至关重要。我们使用不同的组学方法，确定了 Zeste 增强子同源物 2（EZH2）是损伤肺上皮纤维化的关键调节因子。上皮损伤导致核转化生长因子-β激活激酶 1（TAK1）的富集，介导 EZH2 磷酸化，促进其从多梳抑制复合物 2（PRC2）中释放。这一过程导致 EZH2、RNA 聚合酶 II（POL2）和核肌动蛋白的转录复合物的建立，协调异常的上皮修复程序。EZH2 从 PRC2 中的释放伴随着 EZH2-EZH1 的转换，以维持非靶基因的 H3K27me3 沉积。上皮 TAK1、EZH2 的缺失或阻止核肌动蛋白流入可减弱纤维化级联反应并恢复呼吸稳态。因此，EZH2 抑制显著改善了肺纤维化小鼠模型的预后。我们的研究结果揭示了 EZH2 的一个重要非典型功能，为纤维化性肺部疾病的新治疗干预铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/fa963cbf3698/EMBR-22-e52785-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/1dc84e769dd2/EMBR-22-e52785-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/aa9de412db77/EMBR-22-e52785-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/7fef3d4c549e/EMBR-22-e52785-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/72fc7893d7c3/EMBR-22-e52785-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/687775f822a4/EMBR-22-e52785-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/62fe140ab844/EMBR-22-e52785-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/c58e0a0bdc33/EMBR-22-e52785-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/f1270016f6ad/EMBR-22-e52785-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/fa963cbf3698/EMBR-22-e52785-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/1dc84e769dd2/EMBR-22-e52785-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/aa9de412db77/EMBR-22-e52785-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/7fef3d4c549e/EMBR-22-e52785-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/72fc7893d7c3/EMBR-22-e52785-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/687775f822a4/EMBR-22-e52785-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/62fe140ab844/EMBR-22-e52785-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/c58e0a0bdc33/EMBR-22-e52785-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/f1270016f6ad/EMBR-22-e52785-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b13/8339687/fa963cbf3698/EMBR-22-e52785-g008.jpg

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