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

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

PROVIDER: PRJNA1041827 | ENA |

REPOSITORIES: ENA

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

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

2024-05-01 | GSE248151 | GEO

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

Role of nitric oxide and nitric oxide synthase isoforms in pulmonary emphysema.

Project description:The purpose of this study is to comprehensively elucidate the role of nitric oxide and nitric oxide synthase isoforms in pulmonary emphysema using cap analysis of gene expression (CAGE) sequencing.

2021-01-18 | GSE164521 | GEO

Ten-eleven translocation (Tet) methylcytosine dioxygenases dependent viral DNA demethylation mediates in vivo hepatitis B virus (HBV) biosynthesis

Project description:Liver-specific ten-eleven translocation methylcytosine dioxygenases 2 and 3 (Tet2 plus Tet3)-deficient hepatitis B virus (HBV) transgenic mice fail to support viral biosynthesis. The levels of viral transcription and replication intermediates are dramatically reduced. Hepatitis B core antigen (HBcAg) is only observed in a very limited number of pericentral hepatocytes in a pattern that is similar to glutamate-ammonia ligase (Glul), a -catenin target gene. HBV transcript abundance in Tet-deficient mice resembles that observed in wild-type neonatal mice. Furthermore, the RNA levels of several -catenin target genes including Glul, Lhpp, Notun, Oat, Slc1a2 and Tbx3, in Tet-deficient mice was also similar to that observed in wild-type neonatal mice. As HBV transcription is regulated by -catenin, these finding support the suggestion that neonatal Tet-deficiency might limit -catenin target gene expression, limiting viral biosynthesis. Additionally, HBV transgene DNA displays increased 5-methylcytosine (5mC) frequency at CpG sequences consistent with neonatal Tet-deficiency being responsible for decreased developmental viral DNA demethylation mediated by 5mC oxidation to 5-hydroxymethylcytosine (5hmC), a process that might be responsible for the reduction in cellular -catenin target gene expression and viral transcription and replication.

2023-11-29 | GSE242448 | GEO

Ten-eleven translocation proteins modulate the response to environmental stress in mice

Project description:Ten-eleven translocation proteins modulate the response to environmental stress in mice

| PRJNA415948 | ENA

Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2

Project description:Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2

| PRJNA704360 | ENA