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Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Author

Listed:
  • Marianne B. Palczewski

    (University of Illinois Chicago, College of Pharmacy)

  • Hannah Petraitis Kuschman

    (University of Illinois Chicago, College of Pharmacy)

  • Brian M. Hoffman

    (Weinberg College of Arts and Sciences, Northwestern University)

  • Venkatesan Kathiresan

    (Weinberg College of Arts and Sciences, Northwestern University)

  • Hao Yang

    (Weinberg College of Arts and Sciences, Northwestern University)

  • Sharon A. Glynn

    (University of Galway, College of Medicine, Nursing and Health Sciences, School of Medicine)

  • David L. Wilson

    (Stanford University, School of Humanities and Sciences)

  • Eric T. Kool

    (Stanford University, School of Humanities and Sciences)

  • William R. Montfort

    (University of Arizona)

  • Jenny Chang

    (Weill Cornell Medical College)

  • Aydolun Petenkaya

    (University of Illinois Chicago, College of Engineering)

  • Constantinos Chronis

    (University of Illinois Chicago, College of Medicine)

  • Thomas R. Cundari

    (University of North Texas)

  • Sushma Sappa

    (University of Pittsburgh)

  • Kabirul Islam

    (University of Pittsburgh)

  • Daniel W. McVicar

    (National Cancer Institute, Center for Cancer Research)

  • Yu Fan

    (Center for Biomedical Informatics and Information Technology)

  • Qingrong Chen

    (Center for Biomedical Informatics and Information Technology)

  • Daoud Meerzaman

    (National Cancer Institute, Center for Cancer Research)

  • Michael Sierk

    (National Cancer Institute, Center for Cancer Research)

  • Douglas D. Thomas

    (University of Illinois Chicago, College of Pharmacy)

Abstract

DNA methylation at cytosine bases (5-methylcytosine, 5mC) is a heritable epigenetic mark regulating gene expression. While enzymes that metabolize 5mC are well-characterized, endogenous signaling molecules that regulate DNA methylation machinery have not been described. We report that physiological nitric oxide (NO) concentrations reversibly inhibit the DNA demethylases TET and ALKBH2 by binding to the mononuclear non-heme iron atom forming a dinitrosyliron complex (DNIC) and preventing cosubstrates from binding. In cancer cells treated with exogenous NO, or endogenously synthesizing NO, 5mC and 5-hydroxymethylcytosine (5hmC) increase, with no changes in DNA methyltransferase activity. 5mC is also significantly increased in NO-producing patient-derived xenograft tumors from mice. Genome-wide methylome analysis of cells chronically treated with NO (10 days) shows enrichment of 5mC and 5hmC at gene-regulatory loci, correlating with altered expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a unique epigenetic role for NO.

Suggested Citation

  • Marianne B. Palczewski & Hannah Petraitis Kuschman & Brian M. Hoffman & Venkatesan Kathiresan & Hao Yang & Sharon A. Glynn & David L. Wilson & Eric T. Kool & William R. Montfort & Jenny Chang & Aydolu, 2025. "Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56928-1
    DOI: 10.1038/s41467-025-56928-1
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    References listed on IDEAS

    as
    1. Lanfeng Wang & Yu Zhou & Liang Xu & Rui Xiao & Xingyu Lu & Liang Chen & Jenny Chong & Hairi Li & Chuan He & Xiang-Dong Fu & Dong Wang, 2015. "Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex," Nature, Nature, vol. 523(7562), pages 621-625, July.
    2. Liu Yang & San-Jian Yu & Qi Hong & Yu Yang & Zhi-Ming Shao, 2015. "Reduced Expression of TET1, TET2, TET3 and TDG mRNAs Are Associated with Poor Prognosis of Patients with Early Breast Cancer," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-10, July.
    3. Peter L. Roach & Ian J. Clifton & Charles M. H. Hensgens & Norio Shibata & Christopher J. Schofield & Janos Hajdu & Jack E. Baldwin, 1997. "Structure of isopenicillinN synthase complexed with substrate and the mechanism ofpenicillin formation," Nature, Nature, vol. 387(6635), pages 827-830, June.
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