Vitamin C regulates Schwann cell myelination by promoting DNA demethylation of pro-myelinating genes
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE137139 | GEO | 2020/09/09
REPOSITORIES: GEO
Similar Datasets
Project description:Vitamin C regulates Schwann cell myelination by promoting DNA demethylation of pro-myelinating genes
| PRJNA564620 | ENA
Project description:Ascorbic acid (vitamin C) is critical for Schwann cells to myelinate peripheral nerve axons during development and remyelination after injury. However, its exact mechanism remains elusive. Vitamin C is a dietary nutrient that was recently discovered to promote active DNA demethylation. Schwann cell myelination is characterized by global DNA demethylation in vivo and may therefore be regulated by vitamin C. We found that vitamin C induces a massive transcriptomic shift (n = 3,848 genes) in primary cultured Schwann cells while simultaneously producing a global increase in genomic 5-hydroxymethylcytosine (5hmC), a DNA demethylation intermediate which regulates transcription. Vitamin C up-regulates 10 pro-myelinating genes which exhibit elevated 5hmC content in both the promoter and gene body regions of these loci following treatment. Using a mouse model of human vitamin C metabolism, we found that maternal dietary vitamin C deficiency causes peripheral nerve hypomyelination throughout early development in resulting offspring. Additionally, dietary vitamin C intake regulates the expression of myelin-related proteins such as periaxin (PRX) and myelin basic protein (MBP) during development and remyelination after injury in mice. Taken together, these results suggest that vitamin C cooperatively promotes myelination through 1) increased DNA demethylation and transcription of pro-myelinating genes, and 2) its known role in stabilizing collagen helices to form the basal lamina that is necessary for myelination.
| S-EPMC7530063 | biostudies-literature
Project description:RNA sequencing of sorted mouse Schwann cells expressing YFP due to P0Cre-mediated recombination. The plotting of side scatter versus eYFP fluorescence generates 2 semi-detached eYFP+ clouds of cells, which further enables the enriched selection of myelinating Schwann cells, and of not-myelinating Schwann cells.
2021-04-22 | GSE137947 | GEO
Project description:Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in ES cells. Vitamin C treatment reduces global levels of H3K9me2, but not other histone methylation marks analyzed, as measured by Western blot, immunofluorescence and mass spectrometry. Vitamin C leads to widespread loss of H3K9me2 at large chromosomal domains as well as gene promoters and repeat elements. Vitamin C-induced loss of H3K9me2 occurs rapidly within 24 hours and is reversible. Importantly, we found that the histone demethylases Kdm3a and Kdm3b are required for vitamin C-induced demethylation of H3K9me2. Moreover, we show that vitamin C-induced Kdm3a/b-mediated H3K9me2 demethylation and Tet-mediated DNA demethylation are independent processes. Lastly, we document Kdm3a/b are partially required for the up-regulation of germline genes by vitamin C. These results reveal a specific role for vitamin C in histone demethylation in ES cells, and document that DNA methylation and H3K9me2 cooperate to silence germline genes in pluripotent cells.
2017-06-30 | GSE84009 | GEO
Project description:Maternal Vitamin C is required in vivo for proper DNA demethylation and development of fetal germ cells in a mouse model of Vitamin C deficiency. Withdrawal of Vitamin C from the maternal diet does not affect overall embryonic development but leads to defects in the fetal germline, which persist well after Vitamin C re-supply during late gestation. The transcriptome of germ cells from Vitamin C-deficient embryos is remarkably similar to that of embryos carrying a mutation in Tet1, which is responsible for DNA demethylation and activation of regulators of meiosis. In agreement with these results, Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in Vitamin C during gestation recapitulates a mutation in Tet1 and disrupts germline reprogramming and development. Our work further indicate that the embryonic germline is sensitive to perturbations of the maternal diet, providing a potential intergenerational mechanism for adjusting fecundity to environmental quality.
2019-07-01 | GSE109746 | GEO
Project description:Maternal Vitamin C is required in vivo for proper DNA demethylation and development of fetal germ cells in a mouse model of Vitamin C deficiency. Withdrawal of Vitamin C from the maternal diet does not affect overall embryonic development but leads to defects in the fetal germline, which persist well after Vitamin C re-supply during late gestation. The transcriptome of germ cells from Vitamin C-deficient embryos is remarkably similar to that of embryos carrying a mutation in Tet1, which is responsible for DNA demethylation and activation of regulators of meiosis. In agreement with these results, Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in Vitamin C during gestation recapitulates a mutation in Tet1 and disrupts germline reprogramming and development. Our work further indicate that the embryonic germline is sensitive to perturbations of the maternal diet, providing a potential intergenerational mechanism for adjusting fecundity to environmental quality.
2019-07-01 | GSE109745 | GEO
Project description:Maternal Vitamin C is required in vivo for proper DNA demethylation and development of fetal germ cells in a mouse model of Vitamin C deficiency. Withdrawal of Vitamin C from the maternal diet does not affect overall embryonic development but leads to defects in the fetal germline, which persist well after Vitamin C re-supply during late gestation. The transcriptome of germ cells from Vitamin C-deficient embryos is remarkably similar to that of embryos carrying a mutation in Tet1, which is responsible for DNA demethylation and activation of regulators of meiosis. In agreement with these results, Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in Vitamin C during gestation recapitulates a mutation in Tet1 and disrupts germline reprogramming and development. Our work further indicate that the embryonic germline is sensitive to perturbations of the maternal diet, providing a potential intergenerational mechanism for adjusting fecundity to environmental quality.
2019-07-01 | GSE125496 | GEO
Project description:Maternal Vitamin C is required in vivo for proper DNA demethylation and development of fetal germ cells in a mouse model of Vitamin C deficiency. Withdrawal of Vitamin C from the maternal diet does not affect overall embryonic development but leads to defects in the fetal germline, which persist well after Vitamin C re-supply during late gestation. The transcriptome of germ cells from Vitamin C-deficient embryos is remarkably similar to that of embryos carrying a mutation in Tet1, which is responsible for DNA demethylation and activation of regulators of meiosis. In agreement with these results, Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in Vitamin C during gestation recapitulates a mutation in Tet1 and disrupts germline reprogramming and development. Our work further indicate that the embryonic germline is sensitive to perturbations of the maternal diet, providing a potential intergenerational mechanism for adjusting fecundity to environmental quality.
2019-07-01 | GSE125495 | GEO
Project description:Dendritic cells (DCs) are central in immune responses, bridging the adaptive and innate systems. The study of the in vitro differentiation of DCs from monocytes provides both an in-depth understanding of the analogous in vivo process and a potential source for cancer cell therapy. Active DNA demethylation has been previously reported to be crucial in DC differentiation. Vitamin C, an essential nutrient, is a known cofactor of ten-eleven translocation (TET) enzymes, which drive active demethylation. Currently, the effects of vitamin C treatment on human immune cells are poorly understood. In this study, we have analyzed the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. We have detected extensive demethylation produced by vitamin C treatment, together with concordant gene expression changes during DC maturation. p65, a component of NF-kB, interacts with TET2 and produces both vitamin C-mediated gene upregulation and DNA demethylation during DC maturation, as demonstrated by chemical inhibition. Moreover, vitamin C increases TNFβ production in DCs through p65, in concordance with the upregulation of its coding gene and DNA demethylation of adjacent CpGs. Finally, vitamin C increases DC's ability to stimulate the proliferation of autologous antigen-specific T cells. This work provides a potential strategy for the improvement of cell therapies based on monocyte-derived DCs, as well as a feasible mechanism of action for intravenous high-dose vitamin C treatment in patients.
2022-10-06 | GSE203461 | GEO
Project description:Dendritic cells (DCs) are central in immune responses, bridging the adaptive and innate systems. The study of the in vitro differentiation of DCs from monocytes provides both an in-depth understanding of the analogous in vivo process and a potential source for cancer cell therapy. Active DNA demethylation has been previously reported to be crucial in DC differentiation. Vitamin C, an essential nutrient, is a known cofactor of ten-eleven translocation (TET) enzymes, which drive active demethylation. Currently, the effects of vitamin C treatment on human immune cells are poorly understood. In this study, we have analyzed the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. We have detected extensive demethylation produced by vitamin C treatment, together with concordant gene expression changes during DC maturation. p65, a component of NF-kB, interacts with TET2 and produces both vitamin C-mediated gene upregulation and DNA demethylation during DC maturation, as demonstrated by chemical inhibition. Moreover, vitamin C increases TNFβ production in DCs through p65, in concordance with the upregulation of its coding gene and DNA demethylation of adjacent CpGs. Finally, vitamin C increases DC's ability to stimulate the proliferation of autologous antigen-specific T cells. This work provides a potential strategy for the improvement of cell therapies based on monocyte-derived DCs, as well as a feasible mechanism of action for intravenous high-dose vitamin C treatment in patients.
2022-10-06 | GSE203460 | GEO