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Decreased nuclear ascorbate accumulation accompanied with altered genomic methylation pattern in fibroblasts from arterial tortuosity syndrome patients

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Abstract
Ascorbate requiring Fe2+/2-oxoglutarate-dependent dioxygenases located in the nucleoplasm have been shown to participate in epigenetic regulation of gene expression via histone and DNA demethylation. Transport of dehydroascorbic acid is impaired in the endomembranes of fibroblasts from arterial tortuosity syndrome (ATS) patients, due to the mutation in the gene coding for glucose transporter GLUT10. We hypothesized that altered nuclear ascorbate concentration might be present in ATS fibroblasts, affecting dioxygenase activity and DNA demethylation. Therefore, our aim was to characterize the subcellular distribution of vitamin C, the global and site-specific changes in 5-methylcytosine and 5-hydroxymethylcytosine levels, and the effect of ascorbate supplementation in control and ATS fibroblast cultures. Diminished nuclear accumulation of ascorbate was found in ATS fibroblasts upon ascorbate or dehydroascorbic acid addition. Analyzing DNA samples of cultured fibroblasts from controls and ATS patients, a lower global 5-hydroxymethylcytosine level was found in ATS fibroblasts, which could not be significantly modified by ascorbate addition. Investigation of the (hydroxy)methylation status of specific regions in six candidate genes related to ascorbate metabolism and function showed that ascorbate addition could stimulate hydroxymethylation and active DNA demethylation at the PPAR-gamma gene region in control fibroblasts only. The altered DNA hydroxymethylation patterns in patient cells both at the global level and at specific gene regions accompanied with decreased nuclear accumulation of ascorbate suggests the epigenetic role of vitamin C in the pathomechanism of ATS. The present findings represent the first example for the role of vitamin C transport in epigenetic regulation suggesting that ATS is a compartmentalization disease.
Keywords
VITAMIN-C, ENDOPLASMIC-RETICULUM, DEFICIENCY LEADS, 5-HYDROXYMETHYLCYTOSINE, ACID, MUTATIONS, GENERATION, CELLS

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Citation

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Chicago
Németh, Csilla, Zsófia Nemoda, Péter Lőw, Pál Szabó, Erzsébet Horváth, Andy Willaert, Annekatrien Boel, et al. 2019. “Decreased Nuclear Ascorbate Accumulation Accompanied with Altered Genomic Methylation Pattern in Fibroblasts from Arterial Tortuosity Syndrome Patients.” Oxidative Medicine and Cellular Longevity.
APA
Németh, C., Nemoda, Z., Lőw, P., Szabó, P., Horváth, E., Willaert, A., Boel, A., et al. (2019). Decreased nuclear ascorbate accumulation accompanied with altered genomic methylation pattern in fibroblasts from arterial tortuosity syndrome patients. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY.
Vancouver
1.
Németh C, Nemoda Z, Lőw P, Szabó P, Horváth E, Willaert A, et al. Decreased nuclear ascorbate accumulation accompanied with altered genomic methylation pattern in fibroblasts from arterial tortuosity syndrome patients. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY. 2019;
MLA
Németh, Csilla et al. “Decreased Nuclear Ascorbate Accumulation Accompanied with Altered Genomic Methylation Pattern in Fibroblasts from Arterial Tortuosity Syndrome Patients.” OXIDATIVE MEDICINE AND CELLULAR LONGEVITY (2019): n. pag. Print.
@article{8602694,
  abstract     = {Ascorbate requiring Fe2+/2-oxoglutarate-dependent dioxygenases located in the nucleoplasm have been shown to participate in epigenetic regulation of gene expression via histone and DNA demethylation. Transport of dehydroascorbic acid is impaired in the endomembranes of fibroblasts from arterial tortuosity syndrome (ATS) patients, due to the mutation in the gene coding for glucose transporter GLUT10. We hypothesized that altered nuclear ascorbate concentration might be present in ATS fibroblasts, affecting dioxygenase activity and DNA demethylation. Therefore, our aim was to characterize the subcellular distribution of vitamin C, the global and site-specific changes in 5-methylcytosine and 5-hydroxymethylcytosine levels, and the effect of ascorbate supplementation in control and ATS fibroblast cultures. Diminished nuclear accumulation of ascorbate was found in ATS fibroblasts upon ascorbate or dehydroascorbic acid addition. Analyzing DNA samples of cultured fibroblasts from controls and ATS patients, a lower global 5-hydroxymethylcytosine level was found in ATS fibroblasts, which could not be significantly modified by ascorbate addition. Investigation of the (hydroxy)methylation status of specific regions in six candidate genes related to ascorbate metabolism and function showed that ascorbate addition could stimulate hydroxymethylation and active DNA demethylation at the PPAR-gamma gene region in control fibroblasts only. The altered DNA hydroxymethylation patterns in patient cells both at the global level and at specific gene regions accompanied with decreased nuclear accumulation of ascorbate suggests the epigenetic role of vitamin C in the pathomechanism of ATS. The present findings represent the first example for the role of vitamin C transport in epigenetic regulation suggesting that ATS is a compartmentalization disease.},
  articleno    = {8156592},
  author       = {N{\'e}meth, Csilla and Nemoda,  Zs{\'o}fia and L\unmatched{0151}w, P{\'e}ter and Szab{\'o}, P{\'a}l and Horv{\'a}th, Erzs{\'e}bet and Willaert, Andy and Boel, Annekatrien and Callewaert, Bert and Coucke, Paul and Colombi, Marina and B{\'a}nhegyi, G{\'a}bor and Margittai, {\'E}va},
  issn         = {1942-0900},
  journal      = {OXIDATIVE MEDICINE AND CELLULAR LONGEVITY},
  language     = {eng},
  pages        = {11},
  title        = {Decreased nuclear ascorbate accumulation accompanied with altered genomic methylation pattern in fibroblasts from arterial tortuosity syndrome patients},
  url          = {http://dx.doi.org/10.1155/2019/8156592},
  year         = {2019},
}

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