Decreased Nuclear Ascorbate Accumulation Accompanied with Altered Genomic Methylation Pattern in Fibroblasts from Arterial Tortuosity Syndrome Patients

Oxidative Medicine and Cellular Longevity
Csilla E NémethÉva Margittai

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 ...Continue Reading

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Citations

Oct 18, 2019·Antioxidants & Redox Signaling·Annekatrien BoelÉva Margittai
Nov 28, 2019·International Journal of Molecular Sciences·Beáta LizákÉva Margittai
Oct 2, 2020·Chemical Research in Toxicology·Anatoly Zhitkovich

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Datasets Mentioned

BETA
GSE59989

Methods Mentioned

BETA
biopsies
electrophoresis
acetylation
immunoprecipitation
PCR
ELISA
glycosylation

Software Mentioned

EpiMark
ImageJ
UCSC Genome Browser
iTEM

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