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| Status |
Public on May 01, 2024 |
| Title |
Nitric oxide inhibits ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and Human AlkB homolog 2 (ALKBH2). Physiologic NO concentrations reversibly inhibited TET and ALKBH2 demethylase activity by binding to the mononuclear non-heme iron atom in place of O2 to form a dinitrosyliron complex (DNIC). In cancer cells treated with exogeneous NO, or cells endogenously synthesizing NO, there was a global increase in DNA 5mC, a substrate for TET, that could not be attributed to increased DNA methyltransferase activity. 5mC was also elevated in NO-producing mouse xenograft and patient derived xenograft tumors. Genome-wide DNA methylome analysis of cells chronically treated with NO (10 days) demonstrated enrichment of 5mC at gene-regulatory loci which correlated to the expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO-signaling and represents a novel epigenetic regulatory mechanism of NO.
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| Overall design |
To assess whether nitric oxide (NO) altered gene expression patterns, we conducted RNA sequencing (RNA-seq) on cells treated with 100 uM DETA/NO or untreated for 10 days. For this study we used two triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468.
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| Citation(s) |
38645113 |
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| Submission date |
Nov 17, 2023 |
| Last update date |
May 01, 2024 |
| Contact name |
Douglas David Thomas |
| E-mail(s) |
ddthomas@uic.edu
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| Organization name |
University of Illinois Chicago
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| Department |
Pharmaceutical Sciences
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| Lab |
Thomas Lab
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| Street address |
900 S Ashland Ave
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| City |
Chicago |
| State/province |
Illinois |
| ZIP/Postal code |
60607 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| GSM7906439 |
MDA-MB-231, DETA/NO, 10 days, rep1 |
| GSM7906440 |
MDA-MB-231, DETA/NO, 10 days, rep2 |
| GSM7906441 |
MDA-MB-231, DETA/NO, 10 days, rep3 |
| GSM7906442 |
MDA-MB-468, Control, 10 days, rep1 |
| GSM7906443 |
MDA-MB-468, Control, 10 days, rep2 |
| GSM7906444 |
MDA-MB-468, Control, 10 days, rep3 |
| GSM7906445 |
MDA-MB-468, DETA/NO, 10 days, rep1 |
| GSM7906446 |
MDA-MB-468, DETA/NO, 10 days, rep2 |
| GSM7906447 |
MDA-MB-468, DETA/NO, 10 days, rep3 |
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| This SubSeries is part of SuperSeries: |
| GSE248151 |
Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome |
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| Relations |
| BioProject |
PRJNA1041834 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE248150_RawCounts_HTSeq.txt.gz |
689.7 Kb |
(ftp)(http) |
TXT |
| GSE248150_data_filtered_edger_TMM.csv.gz |
1.5 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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