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

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, Aydolun Petenkaya, Constantinos Chronis, Thomas R. Cundari, Sushma Sappa, Kabirul Islam, Daniel W. McVicar, Yu Fan, Qingrong Chen, Daoud Meerzaman, Michael Sierk and Douglas D. Thomas ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56928-1

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