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Ascorbic acid reprogrames epigenome and epitranscriptome by recycling Fe (III) into Fe (II) in the catalytic cycle of dioxygenases (m6A)

ABSTRACT: Ascorbic acid has been reported to stimulate DNA iterative oxidase TET enzymes, Jumonji C-domain-containinghistone demethylase and potentially RNA m6A demethylase FTO and ALKBH5 as a cofactor. Although ascorbic acid has been widely investigated in reprogramming DNA and histone methylation status in vitro, in cell lines and mouse models, its specific role in the catalytic cycle of dioxygenases remains enigmatic. Here we systematically investigated the stimulation of ascorbic towards TET2, ALKBH3, histone demethylases and FTO. We find that ascorbic acid reprograms epitranscrip-tome by erasing the hypermethylated m6A sites. Biochemistry and Electron spin resonance (ESR) assays demonstrate that ascorbic acid enters the active pocket of dioxygenases, reduces Fe (III), either incorporated upon protein synthesis or generated upon rebounding the hydroxyl radical during oxidation, into Fe (II). Finally, we propose a new model for the catalytic cycle of dioxygenases by adding in the essential dynamic cofactor, ascorbic acid. Ascorbic acid refreshes and regenerates inactive dioxygenase through recycling Fe (III) into Fe (II) in a dynamic “hit-and-run” manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242758 | GEO | 2024/02/01

REPOSITORIES: GEO

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Ascorbic acid reprogrames epigenome and epitranscriptome by recycling Fe (III) into Fe (II) in the catalytic cycle of dioxygenases (RNA-Seq)

Project description:Ascorbic acid has been reported to stimulate DNA iterative oxidase TET enzymes, Jumonji C-domain-containinghistone demethylase and potentially RNA m6A demethylase FTO and ALKBH5 as a cofactor. Although ascorbic acid has been widely investigated in reprogramming DNA and histone methylation status in vitro, in cell lines and mouse models, its specific role in the catalytic cycle of dioxygenases remains enigmatic. Here we systematically investigated the stimulation of ascorbic towards TET2, ALKBH3, histone demethylases and FTO. We find that ascorbic acid reprograms epitranscrip-tome by erasing the hypermethylated m6A sites. Biochemistry and Electron spin resonance (ESR) assays demonstrate that ascorbic acid enters the active pocket of dioxygenases, reduces Fe (III), either incorporated upon protein synthesis or generated upon rebounding the hydroxyl radical during oxidation, into Fe (II). Finally, we propose a new model for the catalytic cycle of dioxygenases by adding in the essential dynamic cofactor, ascorbic acid. Ascorbic acid refreshes and regenerates inactive dioxygenase through recycling Fe (III) into Fe (II) in a dynamic “hit-and-run” manner.

2024-02-01 | GSE242759 | GEO

Ascorbic acid induces transient global active chromatin remodelling, providing clues for its anti-cancer effect

Project description:In addition to the role of antioxidant, ascorbic acid (reducing Vitamin C) is an important cofactor for Fe2+ and α-ketoglutarate (α-KG) dependent dioxygenases (Fe2+/α-KGDDs) that comprise many diverse enzymes, including collagen prolyl hydroxylases, jmjC (Jumonji C) domain containing histone demethylases, Ten-eleven translocation (TET) 5-methyl cytosine (5mC) dioxygenases, and N6-methyl adenosine (m6A) demethylase FTO and ALKBH5. Ascorbic acid was reported to induce global epigenetic reprogramming. Here we optimized the library construction flow chart of single-stranded DNA profiling method KAS-seq and utilized KAS-seq to profile transient chromatin states changes upon ascorbic acid treatment for 10 min. We identified several critical pathways affected by ascorbic acid treatment, providing some clues for explaining the reported positive impact of anti-cancer, anti-depression, and anti-obesity for taking ascorbic acid.

2023-07-25 | GSE237843 | GEO

FTO regulates adult neurogenesis through modulating the dynamics of N6-methyladenosine

Project description:Fat mass and obesity-associated gene (FTO) is a member of the Fe (II) and oxoglutarate-dependent AlkB oxygenase family, and has been linked to obesity and intellectual disability. However, the role of FTO in neurodevelopment and neurogenesis remains largely unknown. Here, we show that FTO is expressed in adult neural stem cells (aNSCs) and neurons, and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to the decreased brain size and body weight. We found that FTO deficiency could reduce the proliferation and neuronal differentiation of aNSCs in vivo, which leads to the impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we further performed the genome-wide m6A profiling and observed the dynamic m6A modification during postnatal neurodevelopment. The loss of FTO could lead to the altered m6A modifications on the mRNAs of several key components of BDNF pathway. These results together suggest that FTO play important roles in neurogenesis and learning and memory.

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Next Generation Sequencing and m6A sequencing Facilitates Quantitative Analysis of Wild Type and genetic FTO knockdown ccRCC cells Transcriptomes

Project description:Purpose: FTO is an N6-methyladenosine (m6A) RNA demethylase. The goals of this study are to to identify functional mRNA targets of FTO m6A demethylase activity in VHL deficient ccRCC cells. We performed transcriptome wide m6A sequencing and RNA sequencing analysis of two independent FTO deficient and wild type ccRCC cell lines. Methods: We performed transcriptome wide m6A sequencing and RNA sequencing analysis of two independent FTO deficient (shFTO#2 and shFTO#5) and wild type ccRCC cell lines. Results: Analysis using exomePeak identified a total of 20,168 m6A peaks that are different between the shFTO cells and the control cells. A total of 2,680 and 4,049 m6A peaks showed a significant increase and decrease (p < 0.05), respectively, in abundance (normalized to input), in shFTO cells relative to Ctrl_cells, and they were thus termed hyper- and hypo-methylated m6A peaks, respectively. Through integrative analysis of the RNA-seq data, we identified 459 hypermethylated m6A peaks the RNA transcripts of which were significantly (p < 0.05) downregulated (255; Hyper-down) or upregulated (204; Hyper-up) in shFTO cells relative to Ctrl cells (Figure XB). Conclusions: Our study represents the first detailed analysis of FTO driving transcriptomes, with biologic replicates, generated by RNA-seq technology and m6A sequencing. Our results confirmed the functional role of FTO in mRNA demethylase and identify the targets of FTO. We conclude that FTO plays important role in mRNA destiny determination by m6A demethylase activity.

2019-10-21 | GSE139123 | GEO

Post-Transcriptional Regulation of HRAS by N6-methyladenosine Drives Tumor Progression

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2022-08-27 | GSE211698 | GEO

Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation [MDA-MB-231-meRIPSeq]

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 | GSE236271 | GEO

Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation [MDA-MB-231-RNASeq]

2024-06-30 | GSE236270 | GEO

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FTO alleviates psoriasis-like dermatitis through the regulation of FN1

Project description:FTO was found to inhibit keratinocyte inflammation and proliferation in both in vitro and in vivo settings, independent of m6A demethylase function. RNA-seq was used to identify fibronectin (FN1,FN) as a potential target for FTO. FTO does not rely on demethylase activity to decrease FN1 expression. The anti-inflammatory and anti-proliferative effects of FTO on psoriasis partly depend on FN1. FTO may regulate the skipping of EDA exon in FN1.

2024-05-31 | GSE253791 | GEO

Knock down of FTO in cervical cancer cells

Project description:FTO, an N6-methyladenosine (m6A) demethylase, can promote cervical cancer cell proliferation and migration. RNA-sequencing of SiHa cells with FTO knockdown was conducted to dissect the differentially expressed genes and the potential mechanism of FTO in cervical cancer.

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