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Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248151 | GEO | 2024/05/01

REPOSITORIES: GEO

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Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [oxRRBS]

Project description: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.

2024-05-01 | GSE248149 | GEO

Nitric oxide inhibits ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [RNA-seq]

2024-05-01 | GSE248150 | GEO

Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome

Project description:Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome

| PRJNA1041827 | ENA

Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [oxRRBS]

Project description:Nitric oxide inhibits Ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [oxRRBS]

| PRJNA1041835 | ENA

Nitric oxide inhibits ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [RNA-seq]

Project description:Nitric oxide inhibits ten-eleven translocation DNA demethylase activity to regulate 5mC and 5hmC across the genome [RNA-seq]

| PRJNA1041834 | ENA

Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-06-30 | GSE236272 | GEO

Nitric oxide inhibits FTO demethylase activity to regulate N<sup>6</sup>-methyladenosine mRNA methylation.

Project description:N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. Demethylation of m6A on mRNA is catalyzed by the enzyme fat mass and obesity-associated protein (FTO), a member of the nonheme Fe(II) and 2-oxoglutarate (2-OG)-dependent family of dioxygenases. FTO activity and m6A-mRNA are dysregulated in multiple diseases including cancers, yet endogenous signaling molecules that modulate FTO activity have not been identified. Here we show that nitric oxide (NO) is a potent inhibitor of FTO demethylase activity by directly binding to the catalytic iron center, which causes global m6A hypermethylation of mRNA in cells and results in gene-specific enrichment of m6A on mRNA of NO-regulated transcripts. Both cell culture and tumor xenograft models demonstrated that endogenous NO synthesis can regulate m6A-mRNA levels and transcriptional changes of m6A-associated genes. These results build a direct link between NO and m6A-mRNA regulation and reveal a novel signaling mechanism of NO as an endogenous regulator of the epitranscriptome.

| S-EPMC10623363 | biostudies-literature

Ten-Eleven Translocation 2 regulates adult neurogenesis through modulating 5mC oxidation dynamics at distinct regulatory elements

Project description:Emerging evidence suggests that various epigenetic mechanisms play important roles in regulating adult neurogenesis. Ten-Eleven Translocation (Tet) proteins, the 5mC dioxygenases, could convert 5mC stepwise to 5-hydroxymethylcytosine (5hmC) and its further oxidation products, which constitute active DNA demethylation pathway. Here we show that unlike embryonic stem cells, 5hmC is acquired upon differentiation of adult neural stem cells (NSCs). The loss of Tet2 in proliferating NSCs significantly decreases their 5hmC abundance and partially blocks the acquisition of 5hmC upon differentiation, leading to the increased proliferation and reduced differentiation both in vitro and in vivo. This impaired neurogenesis process results in a defect of learning and memory as well as depressive behavior in Tet2-/- animals. Biochemical and epigenomic analyses reveal that transcription factor Forkhead box O3 (Foxo3a) physically interacts with Tet2 and orchestrates with various forms cytosine modifications to regulate different cohorts of gene expression through distinct mechanisms. These data together establish a novel and fundamental role of Tet2 in neurogenesis by coordinating with Foxo3a to epigenetically regulate the expression of key genes involved in neurogenesis.

2017-07-03 | GSE65994 | GEO

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Project description:BackgroundMedulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.ResultsWe investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.ConclusionsThese results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.

| S-EPMC8082834 | biostudies-literature

Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation [MDA-MB-468-RNASeq]

Project description:Here we show that nitric oxide (NO) is a potent inhibitor of FTO demethylase activity by directly binding to the catalytic iron center, which causes global m6A hypermethylation of mRNA in cells and results in gene-specific enrichment of m6A on mRNA of NO-regulated transcripts. Both cell culture and tumor xenograft models demonstrated that endogenous NO synthesis can regulate m6A-mRNA levels and transcriptional changes of m6A-associated genes. These results build a direct link between NO and m6A-mRNA regulation and reveal a novel signaling mechanism of NO as an endogenous regulator of the epitranscriptome.

2024-06-30 | GSE236269 | GEO

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