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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Data availability
The RNA-Sequencing, ChIP-Sequencing and ATAC-Sequencing data have been deposited into the Gene Expression Omnibus (accession code GSE101383, GSE79423, GSE197086 and GSE181944). All other data supporting the findings of this study are available from the corresponding author on reasonable request.
References
Mamik MK, Power C. Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts. Brain. 2017;140:2273–85.
Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.
Man SM. Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat Rev Gastroenterol Hepatol. 2018;15:721–37.
Rathinam VA, Vanaja SK, Fitzgerald KA. Regulation of inflammasome signaling. Nat Immunol. 2012;13:333–42.
He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41:1012–21.
Dick MS, Sborgi L, Ruhl S, Hiller S, Broz P. ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nat Commun. 2016;7:11929.
Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol. 2013;14:1247–55.
Zhang P, Cao L, Zhou R, Yang X, Wu M. The lncRNA Neat1 promotes activation of inflammasomes in macrophages. Nat Commun. 2019;10:1495.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–49.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–29.
Reijm EA, Timmermans AM, Look MP, Meijer-van Gelder ME, Stobbe CK, van Deurzen CHM, et al. High protein expression of EZH2 is related to unfavorable outcome to tamoxifen in metastatic breast cancer. Ann Oncol. 2014;25:2185–90.
Eich ML, Athar M, Ferguson JE 3rd, Varambally S. EZH2-targeted therapies in cancer: hype or a reality. Cancer Res. 2020;80:5449–58.
Yap TA, Winter JN, Giulino-Roth L, Longley J, Lopez J, Michot JM, et al. Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors. Clin Cancer Res. 2019;25:7331–39.
Zhang X, Wang Y, Yuan J, Li N, Pei S, Xu J, et al. Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. J Exp Med. 2018;215:1365–82.
Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH, et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol. 2015;16:505–16.
Man SM, Kanneganti TD. Regulation of inflammasome activation. Immunol Rev. 2015;265:6–21.
Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.
Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018;10:eaah4066.
Boyer LA, Latek RR, Peterson CL. The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol. 2004;5:158–63.
Campagno KE, Mitchell CH. The P2X(7) receptor in microglial cells modulates the endolysosomal axis, autophagy, and phagocytosis. Front Cell Neurosci. 2021;15:645244.
Kim J, Lee Y, Lu X, Song B, Fong KW, Cao Q, et al. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 2018;25:2808–20.e4.
Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389:349–52.
Gräff J, Tsai LH. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013;14:97–111.
Li P, Spann NJ, Kaikkonen MU, Lu M, Oh DY, Fox JN, et al. NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell. 2013;155:200–14.
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014;17:513–21.
Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014;7:1443–55.
Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, et al. SREBP1 contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism. Cell Metab. 2017;25:412–27.
Adriaens C, Standaert L, Barra J, Latil M, Verfaillie A, Kalev P, et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med. 2016;22:861–8.
Mello SS, Sinow C, Raj N, Mazur PK, Bieging-Rolett K, Broz DK, et al. Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes Dev. 2017;31:1095–108.
Nakamura K, Zhang M, Kageyama S, Ke B, Fujii T, Sosa RA, et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol. 2017;67:1232–42.
Sugimoto K, Toyoshima H, Sakai R, Miyagawa K, Hagiwara K, Ishikawa F, et al. Frequent mutations in the p53 gene in human myeloid leukemia cell lines. Blood. 1992;79:2378–83.
Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012;48:491–507.
Li P, Ge J, Li H. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat Rev Cardiol. 2020;17:96–115.
Tan JZ, Yan Y, Wang XX, Jiang Y, Xu HE. EZH2: biology, disease, and structure-based drug discovery. Acta Pharm Sin. 2014;35:161–74.
Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.
Lv Q, Xing Y, Liu J, Dong D, Liu Y, Qiao H, et al. Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation. Acta Pharm Sin B. 2021;11:2880–99.
Rohraff DM, He Y, Farkash EA, Schonfeld M, Tsou PS, Sawalha AH. Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice. Arthritis Rheumatol. 2019;71:1681–90.
Zhang F, Wu L, Qian J, Qu B, Xia S, La T, et al. Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. J Autoimmun. 2016;75:96–104.
Wang Y, Hou L, Yuan X, Xu N, Zhao S, Yang L, et al. LncRNA NEAT1 targets fibroblast-like synoviocytes in rheumatoid arthritis via the miR-410-3p/YY1 axis. Front Immunol. 2020;11:1975.
Wang S, Zuo H, Jin J, Lv W, Xu Z, Fan Y, et al. Long noncoding RNA Neat1 modulates myogenesis by recruiting Ezh2. Cell Death Dis. 2019;10:505.
Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J, et al. EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells. Cancer Res. 2019;79:2009–20.
Zhou J, Nie D, Li J, Du X, Lu Y, Li Y, et al. PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia. Clin Cancer Res. 2018;24:145–57.
Aasland R, Stewart AF, Gibson T. The SANT domain: a putative DNA-binding domain in the SWI-SNF and ADA complexes, the transcriptional co-repressor N-CoR and TFIIIB. Trends Biochem Sci. 1996;21:87–8.
Boyer LA, Langer MR, Crowley KA, Tan S, Denu JM, Peterson CL. Essential role for the SANT domain in the functioning of multiple chromatin remodeling enzymes. Mol Cell. 2002;10:935–42.
Guan X, Shi A, Zou Y, Sun M, Zhan Y, Dong Y, et al. EZH2-mediated microRNA-375 upregulation promotes progression of breast cancer via the inhibition of FOXO1 and the p53 signaling pathway. Front Genet. 2021;12:633756.
He XY, Xiang C, Zhang CX, Xie YY, Chen L, Zhang GX, et al. p53 in the myeloid lineage modulates an inflammatory microenvironment limiting initiation and invasion of intestinal tumors. Cell Rep. 2015;13:888–97.
Zhou CB, Fang JY. The role of pyroptosis in gastrointestinal cancer and immune responses to intestinal microbial infection. Biochim Biophys Acta Rev Cancer. 2019;1872:1–10.
Fang Y, Tian S, Pan Y, Li W, Wang Q, Tang Y, et al. Pyroptosis: a new frontier in cancer. Biomed Pharmacother. 2020;121:109595.
Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579:415–20.
Wang Y, Fu Z, Li X, Liang Y, Pei S, Hao S, et al. Cytoplasmic DNA sensing by KU complex in aged CD4(+) T cell potentiates T cell activation and aging-related autoimmune inflammation. Immunity. 2021;54:632–47.e9.
Yu T, Gan S, Zhu Q, Dai D, Li N, Wang H, et al. Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24. Nat Commun. 2019;10:4353.
Xiao Y, Zou Q, Xie X, Liu T, Li HS, Jie Z, et al. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J Exp Med. 2017;214:1493–507.
Xu J, Yu T, Pietronigro EC, Yuan J, Arioli J, Pei Y, et al. Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation. PLoS Biol. 2020;18:e3000837.
Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature. 2013;494:90–4.
Zhu Q, Yu T, Gan S, Wang Y, Pei Y, Zhao Q, et al. TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination. J Exp Med. 2020;217:e20192083.
Acknowledgements
We thank Drs. Mian Wu and Pengfei Zhang (University of Science and Technology of China, China) for the generous gift of Neat1-KO mice and Neat1 expression plasmid, and Dr. Jiawei Zhou (Chinese Academy of Sciences, China) for the assistance to generate 6-OHDA-induced PD-like mouse model.
Funding
This research was supported by grants from the National Natural Science Foundation of China (82030041, 82001657), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB39030300), the National Key R&D Program of China (2018YFA0107201, 2018YFA0902703), the programmes from Shanghai Municipal Science and Technology (20XD1424600, 21140905000), China Postdoctoral Science Foundation (2021M702163, 2021M700160, 2021M693272), Special Research Assistant Funding Project of the Chinese Academy of Sciences (QZ), Shanghai Post-doctoral Excellence Program (2021438 for QZ) and CAS Key Laboratory of Tissue Microenvironment and Tumor.
Author information
Authors and Affiliations
Contributions
JY and QZ designed and performed the experiments, prepared the figures, and wrote part of the manuscript; XZ, ZW, GZ, YP, YW, SP and JX contributed to the experiments; NL and JQ contributed to ChIP-seq data analysis; PJ and WL contributed to p65-knockdown Raw2647 cells; CP contributed to mass spectrum analysis; QC supervised a specific subset of the experiments and analyses; YX initiated, designed and supervised this study, prepared the figures and wrote the manuscript. All authors read and approved the final paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics statement
Our studies did not include human participants or human tissue. For the animal studies, experiments were performed according to the protocols approved by the institutional Biomedical Research Ethics Committee, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by A. Degterev
Supplementary information
Rights and permissions
About this article
Cite this article
Yuan, J., Zhu, Q., Zhang, X. et al. Ezh2 competes with p53 to license lncRNA Neat1 transcription for inflammasome activation. Cell Death Differ 29, 2009–2023 (2022). https://doi.org/10.1038/s41418-022-00992-3
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41418-022-00992-3
This article is cited by
-
EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma
Cell Death & Disease (2025)
-
EZH2 elicits CD8+ T-cell desert in esophageal squamous cell carcinoma via suppressing CXCL9 and dendritic cells
Communications Biology (2024)
-
Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application
Signal Transduction and Targeted Therapy (2024)
-
Non-coding RNAs as a Critical Player in the Regulation of Inflammasome in Inflammatory Bowel Diseases; Emphasize on lncRNAs
Cell Biochemistry and Biophysics (2024)
-
Aged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies
Biology Direct (2023)
