The epigenetic role of vitamin C in health and disease

Cellular and Molecular Life Sciences

Volumn 73, Issue 8, 2016, Pages 1645-1658

  Camarena, Vladimir ^a   Wang, Gaofeng ^a,b,c  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF MIAMI   (United States)

Author keywords

DNA methylation; Epigenetics; Histone methylation; JmjC domain containing histone demethylases; Methylcytosine dioxygenase; Scurvy; Vitamin C

Indexed keywords

ASCORBIC ACID; DIOXYGENASE; DNA; DNA GLYCOSYLTRANSFERASE; HISTONE DEMETHYLASE; METHYLCYTOSINE DIOXYGENASE; UNCLASSIFIED DRUG; F BOX PROTEIN; HISTONE; KDM2A PROTEIN, HUMAN;

ASCORBATE DEFICIENCY; ASCORBIC ACID DEFICIENCY; BRAIN REGION; CATALYSIS; DEMETHYLATION; DNA DEMETHYLATION; DNA REPLICATION; DRUG BIOAVAILABILITY; EMBRYO DEVELOPMENT; EPIGENETICS; GENE FREQUENCY; GENETIC VARIABILITY; HUMAN; HYDROXYLATION; INCIDENCE; MYELINATION; NERVE DEGENERATION; PHENOTYPE; POSTNATAL DEVELOPMENT; REVIEW; RISK FACTOR; AGING; DEGENERATIVE DISEASE; DNA METHYLATION; GENETIC EPIGENESIS; GENETICS; METABOLISM; NEOPLASM; PATHOLOGY; PHYSIOLOGY; SCURVY;

AGING; ASCORBIC ACID; ASCORBIC ACID DEFICIENCY; DIOXYGENASES; DNA METHYLATION; EMBRYONIC DEVELOPMENT; EPIGENESIS, GENETIC; F-BOX PROTEINS; HISTONES; HUMANS; JUMONJI DOMAIN-CONTAINING HISTONE DEMETHYLASES; NEOPLASMS; NEURODEGENERATIVE DISEASES; SCURVY;

EID: 84957559320     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2145-x     Document Type: Review

References (167)

1. Agus DB, Gambhir SS, Pardridge WM, Spielholz C, Baselga J, Vera JC, Golde DW (1997) Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest 100:2842-2848
2. Akikusa JD, Garrick D, Nash MC (2003) Scurvy: forgotten but not gone. J Paediatr Child Health 39:75-77
3. Al-Mahdawi S, Virmouni SA, Pook MA (2014) The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases. Front Neurosci 8:397
4. Anthony HM, Schorah CJ (1982) Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br J Cancer 46:354-367
5. Attwood EC, Robey E, Kramer JJ, Ovenden N, Snape S, Ross J, Bradley F (1978) A survey of the haematological, nutritional and biochemical state of the rural elderly with particular reference to vitamin C. Age Ageing 7:46-56
6. Babiarz J, Kane-Goldsmith N, Basak S, Liu K, Young W, Grumet M (2011) Juvenile and adult olfactory ensheathing cells bundle and myelinate dorsal root ganglion axons in culture. Exp Neurol 229:72-79
7. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205-214
8. Bates CJ, Prentice A (1994) Breast milk as a source of vitamins, essential minerals and trace elements. Pharmacol Ther 62:193-220
9. Bhutani N, Burns DM, Blau HM (2011) DNA demethylation dynamics Cell 146:866-872
10. Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A, Lorincz MC, Ramalho-Santos M (2013) Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500:222-226
11. Bradley-Whitman MA, Lovell MA (2013) Epigenetic changes in the progression of Alzheimer's disease. Mech Ageing Dev 134:486-495
12. Brender JD, Werler MM, Kelley KE, Vuong AM, Shinde MU, Zheng Q, Huber JC Jr, Sharkey JR, Griesenbeck JS, Romitti PA, Langlois PH, Suarez L, Canfield MA, The National Birth Defects Prevention, Study (2011) Nitrosatable drug exposure during early pregnancy and neural tube defects in offspring: national birth defects prevention study. Am J Epidemiol 174:1286-1295
13. Buffinton GD, Doe WF (1995) Altered ascorbic acid status in the mucosa from inflammatory bowel disease patients. Free Radic Res 22:131-143
14. Bunge RP, Bunge MB, Eldridge CF (1986) Linkage between axonal ensheathment and basal lamina production by Schwann cells. Annu Rev Neurosci 9:305-328
15. Cahill LE, El-Sohemy A (2009) Vitamin C transporter gene polymorphisms, dietary vitamin C and serum ascorbic acid. J Nutrigenet Nutrigenom 2:292-301
16. Casanueva E, Ripoll C, Tolentino M, Morales RM, Pfeffer F, Vilchis P, Vadillo-Ortega F (2005) Vitamin C supplementation to prevent premature rupture of the chorioamniotic membranes: a randomized trial. Am J Clin Nutr 81:859-863
17. Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M (2013) Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice. Int J Oncol 42:55-64
18. Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M (2011) Ascorbate depletion increases growth and metastasis of melanoma cells in vitamin C deficient mice. Exp Oncol 33:226-230
19. Chan D, Lamande SR, Cole WG, Bateman JF (1990) Regulation of procollagen synthesis and processing during ascorbate-induced extracellular matrix accumulation in vitro. Biochem J 269:175-181
20. Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z, Liu J, Liu J, Wu H, Mao SQ, Mo K, Li Y, Lai K, Qi J, Yao H, Pan G, Xu GL, Pei D (2013) Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 45:1504-1509
21. Chen J, Liu H, Liu J, Qi J, Wei B, Yang J, Liang H, Chen Y, Chen J, Wu Y, Guo L, Zhu J, Zhao X, Peng T, Zhang Y, Chen S, Li X, Li D, Wang T, Pei D (2013) H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet 45:34-42
22. Chung TL, Brena RM, Kolle G, Grimmond SM, Berman BP, Laird PW, Pera MF, Wolvetang EJ (2010) Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cells 28:1848-1855
23. Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M (2014) Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. Neurobiol Aging 35:1334-1344
24. Corpe CP, Tu H, Eck P, Wang J, Faulhaber-Walter R, Schnermann J, Margolis S, Padayatty S, Sun H, Wang Y, Nussbaum RL, Espey MG, Levine M (2010) Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest 120:1069-1083
25. Deicher R, Horl WH (2003) Vitamin C in chronic kidney disease and hemodialysis patients. Kidney Blood Press Res 26:100-106
26. Dickson KM, Gustafson CB, Young JI, Zuchner S, Wang G (2013) Ascorbate-induced generation of 5-hydroxymethylcytosine is unaffected by varying levels of iron and 2-oxoglutarate. Biochem Biophys Res Commun 439:522-527
27. Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A, Levine RL, Nik S, Chen EI, Abeliovich A (2012) Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488:652-655
28. Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA, Fulford AJ, Guan Y, Laritsky E, Silver MJ, Swan GE, Zeisel SH, Innis SM, Waterland RA, Prentice AM, Hennig BJ (2014) Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 5:3746
29. Dror DK, Allen LH (2012) Interventions with vitamins B6, B12 and C in pregnancy. Paediatr Perinat Epidemiol 26(Suppl 1):55-74
30. Elisia I, Kitts DD (2013) Differences in vitamin E and C profile between infant formula and human milk and relative susceptibility to lipid oxidation. Int J Vitam Nutr Res 83:311-319
31. Erichsen HC, Engel SA, Eck PK, Welch R, Yeager M, Levine M, Siega-Riz AM, Olshan AF, Chanock SJ (2006) Genetic variation in the sodium-dependent vitamin C transporters, SLC23A1, and SLC23A2 and risk for preterm delivery. Am J Epidemiol 163:245-254
32. Erichsen HC, Peters U, Eck P, Welch R, Schoen RE, Yeager M, Levine M, Hayes RB, Chanock S (2008) Genetic variation in sodium-dependent vitamin C transporters SLC23A1 and SLC23A2 and risk of advanced colorectal adenoma. Nutr Cancer 60:652-659
33. Fain O, Mathieu E, Thomas M (1998) Scurvy in patients with cancer. BMJ 316:1661-1662
34. Faizallah R, Morris AI, Krasner N, Walker RJ (1986) Alcohol enhances vitamin C excretion in the urine. Alcohol Alcohol 21:81-84
35. Feltri ML, Poitelon Y, Previtali SC (2015) How schwann cells sort axons: new concepts. Neuroscientist. pii:1073858415572361 [Epub ahead of print]
36. Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B (1997) Very old women at highest risk of dementia and Alzheimer's disease: incidence data from the Kungsholmen project. Stockholm Neurol 48:132-138
37. Gao Y, Han Z, Li Q, Wu Y, Shi X, Ai Z, Du J, Li W, Guo Z, Zhang Y (2015) Vitamin C induces a pluripotent state in mouse embryonic stem cells by modulating microRNA expression. FEBS J 282:685-699
38. Gess B, Lohmann C, Halfter H, Young P (2010) Sodium-dependent vitamin C transporter 2 (SVCT2) is necessary for the uptake of l-ascorbic acid into Schwann cells. Glia 58:287-299
39. Gess B, Rohr D, Fledrich R, Sereda MW, Kleffner I, Humberg A, Nowitzki J, Strecker JK, Halfter H, Young P (2011) Sodium-dependent vitamin C transporter 2 deficiency causes hypomyelination and extracellular matrix defects in the peripheral nervous system. J Neurosci 31:17180-17192
40. Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45:106-124
41. Gould BS, Woessner JF (1957) Biosynthesis of collagen; the influence of ascorbic acid on the proline, hydroxyproline, glycine, and collagen content of regenerating guinea pig skin. J Biol Chem 226:289-300
42. Guenette DK, Ritzenthaler JD, Foley J, Jackson JD, Smith BD (1992) DNA methylation inhibits transcription of procollagen alpha 2(I) promoters. Biochem J 283(Pt 3):699-703
43. Guerin P, El Mouatassim S, Menezo Y (2001) Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum Reprod Update 7:175-189
44. Guey LT, Garcia-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M, Rothman N, Vellalta G, Calle ML, Marenne G, Tardon A, Carrato A, Garcia-Closas R, Serra C, Silverman DT, Chanock S, Real FX, Malats N, EPICURO/Spanish Bladder Cancer Study investigators (2010) Genetic susceptibility to distinct bladder cancer subphenotypes. Eur Urol 57:283-292
45. Guo F, Li X, Liang D, Li T, Zhu P, Guo H, Wu X, Wen L, Gu TP, Hu B, Walsh CP, Li J, Tang F, Xu GL (2014) Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15:447-458
46. Gustafson CB, Yang C, Dickson KM, Shao H, Van Booven D, Harbour JW, Liu ZJ, Wang G (2015) Epigenetic reprogramming of melanoma cells by vitamin C treatment. Clin Epigenet 7:51-015-0087-z. eCollection 2015
47. Handelman GJ (2007) Vitamin C deficiency in dialysis patients - are we perceiving the tip of an iceberg? Nephrol Dial Transpl 22:328-331
48. Harris HR, Orsini N, Wolk A (2014) Vitamin C and survival among women with breast cancer: a meta-analysis. Eur J Cancer 50:1223-1231
49. Harrison FE (2012) A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease. J Alzheimers Dis 29:711-726
50. Hata R, Senoo H (1989) l-ascorbic acid 2-phosphate stimulates collagen accumulation, cell proliferation, and formation of a three-dimensional tissuelike substance by skin fibroblasts. J Cell Physiol 138:8-16
51. He XJ, Chen T, Zhu JK (2011) Regulation and function of DNA methylation in plants and animals. Cell Res 21:442-465
52. He X, Kim M, Kim S, Yi S, Rhee Y, Kim T, Lee E, Park C, Dixit S, Harrison FE, Lee S (2015) Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner. Stem Cells 33:1320-1332
53. Hering TM, Kollar J, Huynh TD, Varelas JB, Sandell LJ (1994) Modulation of extracellular matrix gene expression in bovine high-density chondrocyte cultures by ascorbic acid and enzymatic resuspension. Arch Biochem Biophys 314:90-98
54. Hosoya K, Minamizono A, Katayama K, Terasaki T, Tomi M (2004) Vitamin C transport in oxidized form across the rat blood-retinal barrier. Invest Ophthalmol Vis Sci 45:1232-1239
55. Hossein MS, Hashem MA, Jeong YW, Lee MS, Kim S, Kim JH, Koo OJ, Park SM, Lee EG, Park SW, Kang SK, Lee BC, Hwang WS (2007) Temporal effects of α-tocopherol and l-ascorbic acid on in vitro fertilized porcine embryo development. Anim Reprod Sci 100:107-117
56. Hsu CH, Peng KL, Kang ML, Chen YR, Yang YC, Tsai CH, Chu CS, Jeng YM, Chen YT, Lin FM, Huang HD, Lu YY, Teng YC, Lin ST, Lin RK, Tang FM, Lee SB, Hsu HM, Yu JC, Hsiao PW, Juan LJ (2012) TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases. Cell Rep 2:568-579
57. Hu F, Wu Z, Li G, Teng C, Liu Y, Wang F, Zhao Y, Pang D (2015) The plasma level of retinol, vitamins A, C and alpha-tocopherol could reduce breast cancer risk? A meta-analysis and meta-regression. J Cancer Res Clin Oncol 141:601-614
58. Hu J, Cheng D, Gao X, Bao J, Ma X, Wang H (2012) Vitamin C enhances the in vitro development of porcine pre-implantation embryos by reducing oxidative stress. Reprod Domest Anim 47:873-879
59. Huang Y, Tang X, Xie W, Zhou Y, Li D, Zhou Y, Zhu J, Yuan T, Lai L, Pang D, Ouyang H (2011) Vitamin C enhances in vitro and in vivo development of porcine somatic cell nuclear transfer embryos. Biochem Biophys Res Commun 411:397-401
60. Ide K, Yamada H, Umegaki K, Mizuno K, Kawakami N, Hagiwara Y, Matsumoto M, Yoshida H, Kim K, Shiosaki E, Yokochi T, Harada K (2015) Lymphocyte vitamin C levels as potential biomarker for progression of Parkinson's disease. Nutrition 31:406-408
61. Inoue A, Zhang Y (2011) Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334:194
62. Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds (2000) Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. National Academies Press (US), Washington, DC. ISBN-10: 0-309-06949-1, ISBN-10: 0-309-06935-1
63. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129-1133
64. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300-1303
65. Jeong YW, Park SW, Hossein MS, Kim S, Kim JH, Lee SH, Kang SK, Lee BC, Hwang WS (2006) Antiapoptotic and embryotrophic effects of alpha-tocopherol and l-ascorbic acid on porcine embryos derived from in vitro fertilization and somatic cell nuclear transfer. Theriogenology 66:2104-2112
66. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253-262
67. Justin N, De Marco V, Aasland R, Gamblin SJ (2010) Reading, writing and editing methylated lysines on histone tails: new insights from recent structural studies. Curr Opin Struct Biol 20:730-738
68. Kamikawa YF, Donohoe ME (2015) Histone demethylation maintains Prdm14 and Tsix expression and represses xIst in embryonic stem cells. PLoS One 10:e0125626
69. Kere M, Siriboon C, Lo NW, Nguyen NT, Ju JC (2013) Ascorbic acid improves the developmental competence of porcine oocytes after parthenogenetic activation and somatic cell nuclear transplantation. J Reprod Dev 59:78-84
70. Kishimoto Y, Kanai T, Sato K, Lee J, Jeong K, Shimokado K, Maruyama N, Ishigami A (2013) 2013) Insufficient ascorbic acid intake during gestation induces abnormal cardiac dilation in fetal and neonatal SMP30/GNL knockout mice. Pediatr Res 73:578-584
71. Klose RJ, Kallin EM, Zhang Y (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7:715-727
72. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839-843
73. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8:200-213
74. Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472-479
75. Kopp MU, Winterhalter KH, Trueb B (1997) DNA methylation accounts for the inhibition of collagen VI expression in transformed fibroblasts. Eur J Biochem 249:489-496
76. Koshiishi I, Mamura Y, Liu J, Imanari T (1998) Evaluation of an acidic deproteinization for the measurement of ascorbate and dehydroascorbate in plasma samples. Clin Chem 44:863-868
77. Kramer M, Dees C, Huang J, Schlottmann I, Palumbo-Zerr K, Zerr P, Gelse K, Beyer C, Distler A, Marquez VE, Distler O, Schett G, Distler JH (2013) Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis 72:614-620
78. Kranendijk M, Salomons GS, Gibson KM, Van Schaftingen E, Jakobs C, Struys EA (2011) A lymphoblast model for IDH2 gain-of-function activity in d-2-hydroxyglutaric aciduria type II: novel avenues for biochemical and therapeutic studies. Biochim Biophys Acta 1812:1380-1384
79. Krasner N, Dymock IW (1974) Ascorbic acid deficiency in malignant diseases: a clinical and biochemical study. Br J Cancer 30:142-145
80. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929-930
81. Kroeze LI, van der Reijden BA, Jansen JH (2015) 5-Hydroxymethylcytosine: an epigenetic mark frequently deregulated in cancer. Biochim Biophys Acta 1855:144-154
82. Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, Suderman M, Hallett M, Kimmins S (2013) Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun 4:2889
83. Lashley T, Gami P, Valizadeh N, Li A, Revesz T, Balazs R (2014) Alterations in global DNA methylation and hydroxymethylation are not detected in Alzheimer's disease. Neuropathol Appl Neurobiol 41(4):497-506
84. Li Q, Wang HY, Chepelev I, Zhu Q, Wei G, Zhao K, Wang RF (2014) Stage-dependent and locus-specific role of histone demethylase Jumonji D3 (JMJD3) in the embryonic stages of lung development. PLoS Genet 10:e1004524
85. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, Lee CW, Hu D, Lian BQ, Kleffel S, Yang Y, Neiswender J, Khorasani AJ, Fang R, Lezcano C, Duncan LM, Scolyer RA, Thompson JF, Kakavand H, Houvras Y, Zon LI, Mihm MC Jr, Kaiser UB, Schatton T, Woda BA, Murphy GF, Shi YG (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135-1146
86. Luck MR, Jeyaseelan I, Scholes RA (1995) Ascorbic acid and fertility. Biol Reprod 52:262-266
87. Lykkesfeldt J (2007) Ascorbate and dehydroascorbic acid as reliable biomarkers of oxidative stress: analytical reproducibility and long-term stability of plasma samples subjected to acidic deproteinization. Cancer Epidemiol Biomark Prev 16:2513-2516
88. Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN (2000) Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 71:530-536
89. Lyons BL, Schwarz RI (1984) Ascorbate stimulation of PAT cells causes an increase in transcription rates and a decrease in degradation rates of procollagen mRNA. Nucleic Acids Res 12:2569-2579
90. Madruga de Oliveira A, Rondo PH, Mastroeni SS, Oliveira JM (2008) Plasma concentrations of ascorbic acid in parturients from a hospital in Southeast Brazil. Clin Nutr 27:228-232
91. Mahmoodian F, Peterkofsky B (1999) Vitamin C deficiency in guinea pigs differentially affects the expression of type IV collagen, laminin, and elastin in blood vessels. J Nutr 129:83-91
92. Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286:35334-35338
93. Mallol A, Santalo J, Ibanez E (2015) Improved development of somatic cell cloned mouse embryos by vitamin C and latrunculin A. PLoS One 10:e0120033
94. Mamede AC, Tavares SD, Abrantes AM, Trindade J, Maia JM, Botelho MF (2011) The role of vitamins in cancer: a review. Nutr Cancer 63:479-494
95. Mandl J, Szarka A, Banhegyi G (2009) Vitamin C: update on physiology and pharmacology. Br J Pharmacol 157:1097-1110
96. May JM (1998) Ascorbate function and metabolism in the human erythrocyte. Front Biosci 3:d1-d10
97. May JM, Harrison FE (2013) Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal 19:2068-2083
98. McGarvey ML, Baron-Van Evercooren A, Kleinman HK, Dubois-Dalcq M (1984) Synthesis and effects of basement membrane components in cultured rat Schwann cells. Dev Biol 105:18-28
99. Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151:1417-1430
100. Michels AJ, Hagen TM (2004) Vitamin C status decline with age. In: Asard H, May J, Smirnoff N (eds) Vitamin C: its function and biochemistry in animals and plants. Garland Science/BIOS Scientific Publishers, Abingdon, pp 203-228
101. Minor EA, Court BL, Young JI, Wang G (2013) Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem 288:13669-13674
102. Monfort A, Wutz A (2013) Breathing-in epigenetic change with vitamin C. EMBO Rep 14:337-346
103. Mosdol A, Erens B, Brunner EJ (2008) Estimated prevalence and predictors of vitamin C deficiency within UK's low-income population. J Public Health (Oxf) 30:456-460
104. Muller T, Gessi M, Waha A, Isselstein LJ, Luxen D, Freihoff D, Freihoff J, Becker A, Simon M, Hammes J, Denkhaus D, zur Muhlen A, Pietsch T, Waha A (2012) Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas. Am J Pathol 181:675-683
105. Nualart F, Mack L, Garcia A, Cisternas P, Bongarzone ER, Heitzer M, Jara N, Martinez F, Ferrada L, Espinoza F, Baeza V, Salazar K (2014) Vitamin C transporters, recycling and the bystander effect in the nervous system: SVCT2 versus gluts. J Stem Cell Res Ther 4:209
106. Olmedo JM, Yiannias JA, Windgassen EB, Gornet MK (2006) Scurvy: a disease almost forgotten. Int J Dermatol 45:909-913
107. Olsen CL, Bunge RP (1986) Requisites for growth and myelination of urodele sensory neurons in tissue culture. J Exp Zool 238:373-384
108. Peat JR, Dean W, Clark SJ, Krueger F, Smallwood SA, Ficz G, Kim JK, Marioni JC, Hore TA, Reik W (2014) Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation. Cell Rep 9:1990-2000
109. Pereira JA, Lebrun-Julien F, Suter U (2012) Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci 35:123-134
110. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH, Vitamins in Pre-eclampsia (VIP) Trial Consortium (2006) Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 367:1145-1154
111. Prigge ST, Mains RE, Eipper BA, Amzel LM (2000) New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci 57:1236-1259
112. Quaglino D, Fornieri C, Botti B, Davidson JM, Pasquali-Ronchetti I (1991) Opposing effects of ascorbate on collagen and elastin deposition in the neonatal rat aorta. Eur J Cell Biol 54:18-26
113. Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L, Ramsay AJ, Bea S, Pinyol M, Martinez-Trillos A, Lopez-Guerra M, Colomer D, Navarro A, Baumann T, Aymerich M, Rozman M, Delgado J, Gine E, Hernandez JM, Gonzalez-Diaz M, Puente DA, Velasco G, Freije JM, Tubio JM, Royo R, Gelpi JL, Orozco M, Pisano DG, Zamora J, Vazquez M, Valencia A, Himmelbauer H, Bayes M, Heath S, Gut M, Gut I, Estivill X, Lopez-Guillermo A, Puente XS, Campo E, Lopez-Otin C (2011) Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 44:47-52
114. Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res Rev 14:19-30
115. Rhodes K, Rippe RA, Umezawa A, Nehls M, Brenner DA, Breindl M (1994) DNA methylation represses the murine alpha 1(I) collagen promoter by an indirect mechanism. Mol Cell Biol 14:5950-5960
116. Saikhun K, Faisaikarm T, Ming Z, Lu KH, Kitiyanant Y (2008) α-Tocopherol and l-ascorbic acid increase the in vitro development of IVM/IVF swamp buffalo (Bubalus bubalis) embryos. Animal 2:1486-1490
117. Salzer JL (2015) Schwann cell myelination. Cold Spring Harb Perspect Biol 7:a020529
118. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zuniga-Pflucker JC, Mak TW (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488:656-659
119. Schaus R (1957) The ascorbic acid content of human pituitary, cerebral cortex, heart, and skeletal muscle and its relation to age. Am J Clin Nutr 5:39-41
120. Schectman G, Byrd JC, Gruchow HW (1989) The influence of smoking on vitamin C status in adults. Am J Public Health 79:158-162
121. Schjoldager JG, Tveden-Nyborg P, Lykkesfeldt J (2013) Prolonged maternal vitamin C deficiency overrides preferential fetal ascorbate transport but does not influence perinatal survival in guinea pigs. Br J Nutr 110:1573-1579
122. Schjoldager JG, Paidi MD, Lindblad MM, Birck MM, Kjærgaard AB, Dantzer V, Lykkesfeldt J, Tveden-Nyborg P (2014) Maternal vitamin C deficiency during pregnancy results in transient fetal and placental growth retardation in guinea pigs. Eur J Nutr 54(4):667-676
123. Schleicher RL, Carroll MD, Ford ES, Lacher DA (2009) Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 national health and nutrition examination survey (NHANES). Am J Clin Nutr 90:1252-1263
124. Schorah CJ, Wild J, Hartley R, Sheppard S, Smithells RW (1983) The effect of periconceptional supplementation on blood vitamin concentrations in women at recurrence risk for neural tube defect. Br J Nutr 49:203-211
125. Schubeler D (2015) Function and information content of DNA methylation. Nature 517:321-326
126. Sengupta PK, Smith BD (1998) Methylation in the initiation region of the first exon suppresses collagen pro-alpha2(I) gene transcription. Biochim Biophys Acta 1443:75-89
127. Senthilkumari S, Talwar B, Dharmalingam K, Ravindran RD, Jayanthi R, Sundaresan P, Saravanan C, Young IS, Dangour AD, Fletcher AE (2014) Polymorphisms in sodium-dependent vitamin C transporter genes and plasma, aqueous humor and lens nucleus ascorbate concentrations in an ascorbate depleted setting. Exp Eye Res 124:24-30
128. Shen L, Inoue A, He J, Liu Y, Lu F, Zhang Y (2014) Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell Stem Cell 15:459-470
129. Shen L, Wu H, Diep D, Yamaguchi S, D'Alessio AC, Fung HL, Zhang K, Zhang Y (2013) Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153:692-706
130. Shpargel KB, Sengoku T, Yokoyama S, Magnuson T (2012) UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet 8:e1002964
131. Simpson GLW, Ortwerth BJ (2000) The non-oxidative degradation of ascorbic acid at physiological conditions. Biochimica et Biophysica Acta (BBA) Mol Basis Dis 1501:12-24
132. Skibola CF, Bracci PM, Halperin E, Nieters A, Hubbard A, Paynter RA, Skibola DR, Agana L, Becker N, Tressler P, Forrest MS, Sankararaman S, Conde L, Holly EA, Smith MT (2008) Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma. PLoS One 3:e2816
133. Song CX, Szulwach KE, Dai Q, Fu Y, Mao SQ, Lin L, Street C, Li Y, Poidevin M, Wu H, Gao J, Liu P, Li L, Xu GL, Jin P, He C (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153:678-691
134. Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, Munzel M, Wagner M, Muller M, Khan F, Eberl HC, Mensinga A, Brinkman AB, Lephikov K, Muller U, Walter J, Boelens R, van Ingen H, Leonhardt H, Carell T, Vermeulen M (2013) Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152:1146-1159
135. Stadtfeld M, Apostolou E, Ferrari F, Choi J, Walsh RM, Chen T, Ooi SS, Kim SY, Bestor TH, Shioda T, Park PJ, Hochedlinger K (2012) Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nat Genet 44(398-405):S1-S2
136. Struys EA, Jansen EE, Verhoeven NM, Jakobs C (2004) Measurement of urinary d- and l-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-l-tartaric anhydride. Clin Chem 50:1391-1395
137. Swaney P, Thorp J, Allen I (2014) Vitamin C supplementation in pregnancy - does it decrease rates of preterm birth? A systematic review. Am J Perinatol 31:91-98
138. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930-935
139. Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139:1895-1902
140. Tao Y, Zhou B, Xia G, Wang F, Wu Z, Fu M (2004) Exposure to l-ascorbic acid or alpha-tocopherol facilitates the development of porcine denuded oocytes from metaphase I to metaphase II and prevents cumulus cells from fragmentation. Reprod Domest Anim 39:52-57
141. Taylor S, Rath M, Bhutani N (2015) Loss Of Tet1 impairs endochondral ossification in the embryonic growth plate. In: Poster 402 presented at: the 2015 orthopaedic research society's annual meeting in Las Vegas Nevada
142. Taylor SE, Li YH, Wong WH, Bhutani N (2015) Genome-wide mapping of DNA hydroxymethylation in osteoarthritic chondrocytes. Arthritis Rheumatol 67:2129-2140
143. Thompson JP, Simkevich CP, Holness MA, Kang AH, Raghow R (1991) In vitro methylation of the promoter and enhancer of Pro alpha 1(I) collagen gene leads to its transcriptional inactivation. J Biol Chem 266:2549-2556
144. Timpson NJ, Forouhi NG, Brion MJ, Harbord RM, Cook DG, Johnson P, McConnachie A, Morris RW, Rodriguez S, Luan J, Ebrahim S, Padmanabhan S, Watt G, Bruckdorfer KR, Wareham NJ, Whincup PH, Chanock S, Sattar N, Lawlor DA, Davey Smith G (2010) Genetic variation at the SLC23A1 locus is associated with circulating concentrations of l-ascorbic acid (vitamin C): evidence from 5 independent studies with >15,000 participants. Am J Clin Nutr 92:375-382
145. Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, Slieker RC, Stok AP, Thijssen PE, Muller F, van Zwet EW, Bock C, Meissner A, Lumey LH, Eline Slagboom P, Heijmans BT (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 5:5592
146. Torfs CP, Lam PK, Schaffer DM, Brand RJ (1998) Association between mothers' nutrient intake and their offspring's risk of gastroschisis. Teratology 58:241-250
147. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811-816
148. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479-483
149. Tveden-Nyborg P, Johansen LK, Raida Z, Villumsen CK, Larsen JO, Lykkesfeldt J (2009) Vitamin C deficiency in early postnatal life impairs spatial memory and reduces the number of hippocampal neurons in guinea pigs. Am J Clin Nutr 90:540-546
150. Tveden-Nyborg P, Lykkesfeldt J (2013) Does vitamin C deficiency increase lifestyle-associated vascular disease progression? Evidence based on experimental and clinical studies. Antioxid Redox Signal 19:2084-2104
151. Tveden-Nyborg P, Vogt L, Schjoldager JG, Jeannet N, Hasselholt S, Paidi MD, Christen S, Lykkesfeldt J (2012) Maternal vitamin C deficiency during pregnancy persistently impairs hippocampal neurogenesis in offspring of guinea pigs. PLoS One 7:e48488
152. van Robertson WB, Schwartz B (1953) Ascorbic acid and the formation of collagen. J Biol Chem 201:689-696
153. Vissers MC, Bozonet SM, Pearson JF, Braithwaite LJ (2011) Dietary ascorbate intake affects steady state tissue concentrations in vitamin C-deficient mice: tissue deficiency after suboptimal intake and superior bioavailability from a food source (kiwifruit). Am J Clin Nutr 93:292-301
154. Wang C, Lee JE, Cho YW, Xiao Y, Jin Q, Liu C, Ge K (2012) UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci USA 109:15324-15329
155. Wang L, Zhang J, Duan J, Gao X, Zhu W, Lu X, Yang L, Zhang J, Li G, Ci W, Li W, Zhou Q, Aluru N, Tang F, He C, Huang X, Liu J (2014) Programming and inheritance of parental DNA methylomes in mammals. Cell 157:979-991
156. Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G, Pei D (2011) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9:575-587
157. Welstead GG, Creyghton MP, Bilodeau S, Cheng AW, Markoulaki S, Young RA, Jaenisch R (2012) X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner. Proc Natl Acad Sci USA 109:13004-13009
158. Wilson JX (2005) Regulation of vitamin C transport. Annu Rev Nutr 25:105-125
159. Wolbach SB, Howe PR (1926) Intercellular substances in experimental scorbutus. Arch Pathol 1:1-26
160. Wood PM, Schachner M, Bunge RP (1990) Inhibition of Schwann cell myelination in vitro by antibody to the L1 adhesion molecule. J Neurosci 10:3635-3645
161. Wright ME, Andreotti G, Lissowska J, Yeager M, Zatonski W, Chanock SJ, Chow WH, Hou L (2009) Genetic variation in sodium-dependent ascorbic acid transporters and risk of gastric cancer in Poland. Eur J Cancer 45:1824-1830
162. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17-30
163. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, Barbera AJ, Zheng L, Zhang H, Huang S, Min J, Nicholson T, Chen T, Xu G, Shi Y, Zhang K, Shi YG (2011) Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 42:451-464
164. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG (2011) Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147:1498-1510
165. Yin R, Mao SQ, Zhao B, Chong Z, Yang Y, Zhao C, Zhang D, Huang H, Gao J, Li Z, Jiao Y, Li C, Liu S, Wu D, Gu W, Yang YG, Xu GL, Wang H (2013) Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc 135:10396-10403
166. Young JI, Züchner S, Wang G (2015) Regulation of the epigenome by vitamin C. Annu Rev Nutr 35:545-564
167. Zimmermann P, Boeuf S, Dickhut A, Boehmer S, Olek S, Richter W (2008) Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheum 58:2743-2753