2025 - Sustainable Industrial Processing Summit
SIPS2025 Volume 2. Inufusa Intl. Symp. / Oxidative Stress and Technological Innovations in Medicine
| Editors: | F. Kongoli, K. Abe, W. Cho, K. Fukui, S. Hirano, D. Joseph, T. Yoshikawa, J.R. Ribas, N. Tran |
| Publisher: | Flogen Star OUTREACH |
| Publication Year: | 2025 |
| Pages: | 282 pages |
| ISBN: | 978-1-998384-40-2 (CD) |
| ISSN: | 2291-1227 (Metals and Materials Processing in a Clean Environment Series) |
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NITRIC OXIDE INHIBITS TEN-ELEVEN TRANSLOCATION DNA DEMETHYLASES TO REGULATE 5mC AND 5hmC ACROSS THE GENOME
Douglas D. Thomas1;1UNIVERSITY OF ILLINOIS AT CHICAGO, Chicago, United States;
Type of Paper: Keynote
Id Paper: 14
Topic: 54
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. This is the first study to demonstrate that NO is an endogenous regulator of TET activity and DNA methylation which is distinctly different from canonical NO signaling and represents a unique epigenetic role for NO. Our previous work demonstrated that NO is an endogenous regulator of histone post-translational modifications, and mRNA methylation, and here we show an unprecedented functional role for NO in regulating steady-state DNA methylation (and hydroxymethylation). Therefore, in addition to its canonical roles in cell signaling and gene expression, NO should now be recognized as a dominant regulator of the epigenetic landscape.