IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59003-x.html
   My bibliography  Save this article

S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis

Author

Listed:
  • Ashima Sakhuja

    (Pilani Campus)

  • Ritobrata Bhattacharyya

    (Pilani Campus)

  • Yash Tushar Katakia

    (Pilani Campus)

  • Shyam Kumar Ramakrishnan

    (Pilani Campus)

  • Srinjoy Chakraborty

    (Pilani Campus)

  • Hariharan Jayakumar

    (Pilani Campus)

  • Shailesh Mani Tripathi

    (Pilani Campus)

  • Niyati Pandya Thakkar

    (Pilani Campus)

  • Sumukh Thakar

    (Pilani Campus)

  • Sandeep Sundriyal

    (Pilani Campus)

  • Shibasish Chowdhury

    (Pilani Campus)

  • Syamantak Majumder

    (Pilani Campus)

Abstract

Nitric oxide (NO), a versatile bio-active molecule modulates cellular functions through diverse mechanisms including S-nitrosylation of proteins. Herein, we report S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells, which interplays with its stability and functions. We detect a significant reduction in H3K27me3 upon S-nitrosylation of EZH2 as contributed by the early dissociation of SUZ12 from the PRC2. Moreover, S-nitrosylation of EZH2 causes its cytosolic translocation, ubiquitination, and degradation. Further analysis reveal S-nitrosylation of cysteine 329 induces EZH2 instability, whereas S-nitrosylation of cysteine 700 abrogates its catalytic activity. We further show that S-nitrosylation-dependent regulation of EZH2 maintains endothelial homeostasis in both physiological and pathological settings. Molecular dynamics simulation reveals the inability of SUZ12 to efficiently bind to the SAL domain of EZH2 upon S-nitrosylation. Taken together, our study reports S-nitrosylation-dependent regulation of EZH2 and its associated PRC2 complex, thereby influencing the epigenetics of endothelial homeostasis.

Suggested Citation

  • Ashima Sakhuja & Ritobrata Bhattacharyya & Yash Tushar Katakia & Shyam Kumar Ramakrishnan & Srinjoy Chakraborty & Hariharan Jayakumar & Shailesh Mani Tripathi & Niyati Pandya Thakkar & Sumukh Thakar &, 2025. "S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59003-x
    DOI: 10.1038/s41467-025-59003-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59003-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59003-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Nikhil B. Ghate & Sungmin Kim & Yonghwan Shin & Jinman Kim & Michael Doche & Scott Valena & Alan Situ & Sangnam Kim & Suhn K. Rhie & Heinz-Josef Lenz & Tobias S. Ulmer & Shannon M. Mumenthaler & Wooji, 2023. "Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Carol Kilkenny & William J Browne & Innes C Cuthill & Michael Emerson & Douglas G Altman, 2010. "Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research," PLOS Biology, Public Library of Science, vol. 8(6), pages 1-5, June.
    3. Neil Justin & Ying Zhang & Cataldo Tarricone & Stephen R. Martin & Shuyang Chen & Elizabeth Underwood & Valeria De Marco & Lesley F. Haire & Philip A. Walker & Danny Reinberg & Jon R. Wilson & Steven , 2016. "Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    4. Talha Anwar & Caroline Arellano-Garcia & James Ropa & Yu-Chih Chen & Hong Sun Kim & Euisik Yoon & Sierrah Grigsby & Venkatesha Basrur & Alexey I. Nesvizhskii & Andrew Muntean & Maria E. Gonzalez & Kel, 2018. "p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Airi Jo-Watanabe & Toshiki Inaba & Takahiro Osada & Ryota Hashimoto & Tomohiro Nishizawa & Toshiaki Okuno & Sayoko Ihara & Kazushige Touhara & Nobutaka Hattori & Masatsugu Oh-Hora & Osamu Nureki & Tak, 2024. "Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. repec:plo:pone00:0215221 is not listed on IDEAS
    3. M Polyakova & M L Schroeter & B M Elzinga & S Holiga & P Schoenknecht & E R de Kloet & M L Molendijk, 2015. "Brain-Derived Neurotrophic Factor and Antidepressive Effect of Electroconvulsive Therapy: Systematic Review and Meta-Analyses of the Preclinical and Clinical Literature," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-18, November.
    4. repec:plo:pone00:0154657 is not listed on IDEAS
    5. Kimberley E Wever & Carlijn R Hooijmans & Niels P Riksen & Thomas B Sterenborg & Emily S Sena & Merel Ritskes-Hoitinga & Michiel C Warlé, 2015. "Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-17, November.
    6. Julie Rondeaux & Déborah Groussard & Sylvanie Renet & Virginie Tardif & Anaïs Dumesnil & Alphonse Chu & Léa Maria & Théo Lemarcis & Manon Valet & Jean-Paul Henry & Zina Badji & Claire Vézier & Delphin, 2023. "Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Bettina Bert & Céline Heinl & Justyna Chmielewska & Franziska Schwarz & Barbara Grune & Andreas Hensel & Matthias Greiner & Gilbert Schönfelder, 2019. "Refining animal research: The Animal Study Registry," PLOS Biology, Public Library of Science, vol. 17(10), pages 1-12, October.
    8. Xiao-meng Xu & Guang-yan Cai & Ru Bu & Wen-juan Wang & Xue-yuan Bai & Xue-feng Sun & Xiang-mei Chen, 2015. "Beneficial Effects of Caloric Restriction on Chronic Kidney Disease in Rodent Models: A Meta-Analysis and Systematic Review," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-15, December.
    9. Zhongwei Xu & Bingze Xu & Susanna L. Lundström & Àlex Moreno-Giró & Danxia Zhao & Myriam Martin & Erik Lönnblom & Qixing Li & Alexander Krämer & Changrong Ge & Lei Cheng & Bibo Liang & Dongmei Tong & , 2023. "A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. Nathalie Percie du Sert & Viki Hurst & Amrita Ahluwalia & Sabina Alam & Marc T Avey & Monya Baker & William J Browne & Alejandra Clark & Innes C Cuthill & Ulrich Dirnagl & Michael Emerson & Paul Garne, 2020. "The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research," PLOS Biology, Public Library of Science, vol. 18(7), pages 1-12, July.
    11. Vivian Leung & Frédérik Rousseau-Blass & Guy Beauchamp & Daniel S J Pang, 2018. "ARRIVE has not ARRIVEd: Support for the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines does not improve the reporting quality of papers in animal welfare, analgesia or anesthesi," PLOS ONE, Public Library of Science, vol. 13(5), pages 1-13, May.
    12. Sara Weirich & Albert Jeltsch, 2023. "Limited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    13. repec:plo:pone00:0240719 is not listed on IDEAS
    14. Simon Bate & Natasha A Karp, 2014. "A Common Control Group - Optimising the Experiment Design to Maximise Sensitivity," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-12, December.
    15. Laura Maxim & Jeroen P van der Sluijs, 2014. "Qualichem In Vivo : A Tool for Assessing the Quality of In Vivo Studies and Its Application for Bisphenol A," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-16, January.
    16. Pauliina M. Munne & Lahja Martikainen & Iiris Räty & Kia Bertula & Nonappa & Janika Ruuska & Hanna Ala-Hongisto & Aino Peura & Babette Hollmann & Lilya Euro & Kerim Yavuz & Linda Patrikainen & Maria S, 2021. "Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    17. Beverly S Muhlhausler & Frank H Bloomfield & Matthew W Gillman, 2013. "Whole Animal Experiments Should Be More Like Human Randomized Controlled Trials," PLOS Biology, Public Library of Science, vol. 11(2), pages 1-6, February.
    18. repec:plo:pone00:0230038 is not listed on IDEAS
    19. Constance Holman & Sophie K Piper & Ulrike Grittner & Andreas Antonios Diamantaras & Jonathan Kimmelman & Bob Siegerink & Ulrich Dirnagl, 2016. "Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke," PLOS Biology, Public Library of Science, vol. 14(1), pages 1-12, January.
    20. Thirumalai Diraviyam & Bin Zhao & Yuan Wang & Ruediger Schade & Antonysamy Michael & Xiaoying Zhang, 2014. "Effect of Chicken Egg Yolk Antibodies (IgY) against Diarrhea in Domesticated Animals: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(5), pages 1-14, May.
    21. repec:plo:pbio00:2004879 is not listed on IDEAS
    22. Bertha Estrella & Elena N. Naumova & Magda Cepeda & Trudy Voortman & Peter D. Katsikis & Hemmo A. Drexhage, 2019. "Effects of Air Pollution on Lung Innate Lymphoid Cells: Review of In Vitro and In Vivo Experimental Studies," IJERPH, MDPI, vol. 16(13), pages 1-15, July.
    23. Emily M Wong & Fern Tablin & Edward S Schelegle, 2020. "Comparison of nonparametric and parametric methods for time-frequency heart rate variability analysis in a rodent model of cardiovascular disease," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-15, November.
    24. repec:plo:pmed00:1001010 is not listed on IDEAS
    25. repec:plo:pbio00:1002273 is not listed on IDEAS
    26. Martín Bustelo & Martín A Bruno & César F Loidl & Manuel Rey-Funes & Harry W M Steinbusch & Antonio W D Gavilanes & D L A van den Hove, 2020. "Statistical differences resulting from selection of stable reference genes after hypoxia and hypothermia in the neonatal rat brain," PLOS ONE, Public Library of Science, vol. 15(5), pages 1-12, May.
    27. repec:plo:pone00:0134205 is not listed on IDEAS
    28. David Baker & Katie Lidster & Ana Sottomayor & Sandra Amor, 2014. "Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies," PLOS Biology, Public Library of Science, vol. 12(1), pages 1-6, January.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59003-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.