2. Academic Validation
  3. Ezh2 competes with p53 to license lncRNA Neat1 transcription for inflammasome activation

Ezh2 competes with p53 to license lncRNA Neat1 transcription for inflammasome activation

  • Cell Death Differ. 2022 Oct;29(10):2009-2023. doi: 10.1038/s41418-022-00992-3.
Jia Yuan  # 1 2,  Qingchen Zhu  # 2,  Xingli Zhang 2,  Zhenzhen Wen 1,  Guiheng Zhang 2,  Ni Li 2,  Yifei Pei 2,  Yan Wang 2,  Siyu Pei 2 3,  Jing Xu 2,  Pan Jia 2,  Chao Peng 4,  Wei Lu 2,  Jun Qin 2,  Qian Cao 5,  Yichuan Xiao 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, 310016, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3 Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, 201210, China.
  • 5 Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, 310016, China. caoq@zju.edu.cn.
  • 6 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. ycxiao@sibs.ac.cn.
  • # Contributed equally.
PMID: 35568718 DOI: 10.1038/s41418-022-00992-3
Abstract

Inflammasome contributes to the pathogenesis of various inflammatory diseases, but the epigenetic mechanism controlling its activation remains elusive. Here, we found that the Histone Methyltransferase Ezh2 mediates the activation of multiple types of inflammasomes in macrophages/microglia independent of its methyltransferase activity and thus promotes inflammasome-related pathologies. Mechanistically, EZH2 functions through its SANT2 domain to maintain the enrichment of H3K27 acetylation in the promoter region of the long noncoding RNA (lncRNA) Neat1, thereby promoting chromatin accessibility and facilitating p65-mediated transcription of Neat1, which is a critical mediator of inflammasome assembly and activation. In addition, the tumour suppressor protein p53 competes with EZH2 for the same binding region in the Neat1 promoter and thus antagonises Ezh2-induced Neat1 transcription and inflammasome activation. Therefore, loss of EZH2 strongly promotes the binding of p53, which recruits the deacetylase SIRT1 for H3K27 deacetylation of the Neat1 promoter and thus suppresses Neat1 transcription and inflammasome activation. Overall, our study demonstrates an epigenetic mechanism involved in modulating inflammasome activation through an EZH2/p53 competition model and highlights a novel function of EZH2 in maintaining H3K27 acetylation to support lncRNA Neat1 transcription.

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