Regulation of the Epigenome by Vitamin C

Young, Juan I.; Züchner, Stephan; Wang, Gaofeng

doi:10.1146/annurev-nutr-071714-034228

Cited by 276 publications

(263 citation statements)

References 98 publications

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“…Vitamin C is known to be not only a general anti-oxidant, but also a cofactor for a large family of enzymes known as iron-and 2-oxoglutarate-dependent dioxygenases (55). A typical example is the collagen prolyl-4-hydroxylase that is involved in collagen maturation and scurvy.…”

Section: Discussionmentioning

confidence: 99%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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“…Eventual isolation of the respective compounds underlying both vitamins led to Nobel Prizes in Chemistry and Medicine in 1937 [4]. Since this time, a considerable amount of scientific progress (and at times conjecture) has been associated with vitamins A and C, and their respective biological effects touch disciplines as divergent as development and dermatology.One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state.…”

mentioning

confidence: 99%

“…One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state.…”

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confidence: 99%

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Hore

2017

Epigenomics

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Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases -vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment. Figure 1A), and both are associated with a long recorded history. Nightblindness, an early symptom of vitamin A deficiency, and its cure through liver consumption, was known to Egyptians in the prehistoric period [1]. Equally, the debilitating effects of scurvy (vitamin C deficiency) among sailors, and its treatment with oranges, was registered as far back as 1498 [2]. Vitamins A and C also have a lengthy and rich history in scientific literature; in 1753 James Lind described the first controlled clinical trial where various antiscorbutic treatments were tested on British seamen and in 1929, Frederick Gowland Hopkins was co-awarded the Nobel Prize in Medicine for the 'discovery of vitamins' following milk supplementation experiments in vitamin A deficient mice [3]. Eventual isolation of the respective compounds underlying both vitamins led to Nobel Prizes in Chemistry and Medicine in 1937 [4]. Since this time, a considerable amount of scientific progress (and at times conjecture) has been associated with vitamins A and C, and their respective biological effects touch disciplines as divergent as development and dermatology.One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state. Here I review the effects of vitamins A and C on DNA methylation and epigenetic memory in stem cells, and outline their significance for the fields For reprint orders, please contact: reprints@futuremedicine.com

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Section: C-vitaminunclassified

“…Számos enzim kofaktora (prolil-, lizilhidroxiláz), szerepet játszik a koleszterinmetabolizmusban, a citokróm P450 működésében, a neurotranszmitterek, valamint a karnitin szintézisében [6]. Az aszkorbát epigenomikai folyamatokat befolyásol a DNS-és a hisztondemetiláció szabályozásával, mivel esszenciális kofaktora a TET (ten-eleven translocation methylcytosine) dioxigenázoknak, valamint a Jmjc domént tartalmazó hisztondemetilázoknak [7].Kis koncentrációban a C-vitamin redukálja az átmene-ti fémionokat, elősegíti a fémkatalízist a Fenton-reakció-ban, s ezzel a lipidperoxidáció folyamatát katalizálja [2]. Nagy mennyiségű C-vitamin (500 mg/ttkg/nap/4 napon át) a citokróm P450 2E1 a monooxigenázokat indukálja, amely szuperoxidanion-felszabadulással jár [8].…”

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Antioxidánsok – antioxidánssokk: tények és kérdések, 2015

2015

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Az elmúlt években nagy jelentőséget tulajdonítottak az antioxidáns-kezelésnek az oxidatív stresszel összefüggő betegségek megelőzésében, illetve kezelésében. A kezdeti sikerek után azonban bizonyos antioxidánsok nem kívánt hatásairól, toxicitásáról, prooxidáns tulajdonságáról számoltak be (CARET, ATBC vizsgálat). A későbbi metaanalízi-sek eredményei sem támasztották alá az antioxidáns-pótlás alkalmazását az elsődleges és a másodlagos megelőzésben. A szerzők áttekintik az antioxidánsok prooxidáns tulajdonságait, valamint a jelátviteli folyamatokban, a sejtműködés befolyásolásában betöltött szerepüket. Az antioxidánsok kombinált alkalmazása előnyösebb, amelynek lehetséges magyarázatát összegzik a szerzők. Orv. Hetil., 2015, 156(47), 1884-1887.Kulcsszavak: oxidatív stressz, antioxidánsstressz, antioxidáns vitaminok, prooxidáns, jelátviteli folyamatok Antioxidants -antioxidative stress: Facts and questions, 2015In the past years great importance has been attributed to antioxidant therapy in the prevention and treatment of disorders developed in connection with oxidative stress. After initial success, undesirable effects, toxicities, and prooxidant effects of antioxidants were reported [CARET, ATBC study]. In addition, metaanalyses failed to confi rm the role of antioxidant supplementation in the primary and secondary prevention. The authors review the prooxidant effects of antioxidants, and their role in cell signalling and cell process modulation. Finally, the authors summarize possible explanations why combined use of antiooxidants is more favourable. ÖSSZEFOGLALÓ KÖZLEMÉNYRövidítések AP-1 = aktivátor protein-1; HIF-1α = hipoxia indukálta faktor-1α; IGF-IR = inzulinszerű növekedési faktor receptor; NF-κB = nuclear factor kappa-B; PK = proteinkináz; RARE = retinsav; TET = ten-eleven translocation methylcytosine; TGF-α = transzformáló növekedési faktor-α Az utóbbi években kiemelkedő szerepet tulajdonítottak az antioxidáns-kezelésnek a kóros szabad gyökös reakciókkal összefüggő betegségek megelőzésében, illetve kezelésében [1,2]. Legelőször az ATBC, illetve CARET vizsgálatban számoltak be az antioxidánsok nem kívánt hatásairól (retinol, β-karotin-kezelések a tüdőtumor előfordulását növelték) [3]. Későbbi áttekintések sem igazolták a napi ajánlott táplálkozási bevitelt meghaladó mennyiségű ("supra-nutritional") antioxidáns-pótlás hatásosságát az elsődleges és másodlagos megelőzésben [4,5]. C-vitaminA C-vitamin vízoldékony antioxidáns, elektrondonor tulajdonsága révén redukálószer [6]. Számos enzim kofaktora (prolil-, lizilhidroxiláz), szerepet játszik a koleszterinmetabolizmusban, a citokróm P450 működésében, a neurotranszmitterek, valamint a karnitin szintézisében [6]. Az aszkorbát epigenomikai folyamatokat befolyásol a DNS-és a hisztondemetiláció szabályozásával, mivel esszenciális kofaktora a TET (ten-eleven translocation methylcytosine) dioxigenázoknak, valamint a Jmjc domént tartalmazó hisztondemetilázoknak [7].Kis koncentrációban a C-vitamin redukálja az átmene-ti fémionokat, elősegíti a fémkatalízist a Fenton-...

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Regulation of the Epigenome by Vitamin C

Cited by 276 publications

References 98 publications

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Antioxidánsok – antioxidánssokk: tények és kérdések, 2015

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