Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome
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.
Authors
- Yu Fan (ORCID: https://orcid.org/0000-0002-7473-6104)
- Marianne B. Palczewski (ORCID: https://orcid.org/0000-0003-4957-2387)
- Venkatesan Kathiresan (ORCID: https://orcid.org/0000-0002-4151-9154)
- W.R. Montfort (ORCID: https://orcid.org/0000-0001-5776-2530)
- Sharon A. Glynn (ORCID: https://orcid.org/0000-0003-1459-2580)
- Sushma Sappa
- Kabirul Islam (ORCID: https://orcid.org/0000-0002-8680-6130)
- Jenny C. Chang (ORCID: https://orcid.org/0000-0002-0890-9302)
- Thomas R. Cundari (ORCID: https://orcid.org/0000-0003-1822-6473)
- Douglas D. Thomas (ORCID: https://orcid.org/0000-0003-1252-0786)
- Michael Sierk (ORCID: https://orcid.org/0000-0002-0657-0288)
- Daoud Meerzaman (ORCID: https://orcid.org/0000-0002-0129-5256)
- Constantinos Chronis (ORCID: https://orcid.org/0000-0002-7783-8202)
- Daniel W. McVicar (ORCID: https://orcid.org/0000-0002-1112-5111)
- Hannah Petraitis Kuschman (ORCID: https://orcid.org/0000-0002-4291-6338)
- Eric T. Kool (ORCID: https://orcid.org/0000-0002-7310-2935)
- Aydolun Petenkaya
- Brian M. Hoffman (ORCID: https://orcid.org/0000-0002-3100-0746)
- Hao Yang (ORCID: https://orcid.org/0009-0000-2079-7908)
- Qingrong Chen (ORCID: https://orcid.org/0000-0003-1325-6147)
- David L. Wilson (ORCID: https://orcid.org/0000-0002-1922-427X)
Institutions
- Northwestern University (US)
- University of North Texas (US)
- Houston Methodist (US)
- University of Arizona (US)
- University of Illinois Urbana-Champaign (US)
- Illinois College (US)
- University of Pittsburgh (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- American Association of Colleges of Pharmacy (US)
- Cornell University (US)
- University of Illinois Chicago (US)
- Methodist Hospital (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1038/s41467-025-56928-1
- Citations
- 9
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- National Science Foundation
- Breast Cancer Research Foundation
- Science Foundation Ireland
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- University of Illinois at Chicago
- National Cancer Institute
- National Institute of General Medical Sciences
- Division of Chemistry
- Cancer Center, University of Illinois at Chicago