Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism

Zhao, Bailin; Yang, Ying; Wang, Xiaoli; Chong, Zechen; Yin, Ruichuan; Song, Shu Hui; Zhao, Chao; Li, Cuiping; Huang, Hua; Sun, Bao; Wu, Danni; Jin, Kang; Song, Maoyong; Zhu, Ben Zhan; Jiang, Guibin; Danielsen, Jannie M. Rendtlew; Xu, Guo Liang; Yang, Yun; Wang, Hailin

doi:10.1093/nar/gkt1090

Cited by 109 publications

(107 citation statements)

References 59 publications

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“…1E). Although these results challenge the findings reported in the literature (19,(21)(22)(23), they are in complete agreement with the recent finding that redox-active quinones stimulate TET activity in cell culture through reduction of enzyme-free Fe 3+ to Fe 2+ (42). Taken together, these results imply that TET proteins are inherently sensitive to labile iron concentrations in the cell, an idea supported by the fact that the dissociation constant of Fe 2+ and TET1-CD overlaps with the physiological range of labile iron in the cell (Fig.…”

Section: Retinol and Ascorbate Enhance Reprogramming Of Epiblast Stemsupporting

confidence: 88%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

146

127

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Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe 2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

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Section: Retinol and Ascorbate Enhance Reprogramming Of Epiblast Stemsupporting

confidence: 88%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

146

127

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“…As it can be seen in Figure 2, DNA demethylation is carried out by a free radical mechanism catalyzed by the iron-dependent enzymes ten-eleven translocations (TET [105]. Similarly, redox-active quinones, the other superoxide producers activated oxidative conversion of 5mC to 5hmC by the TET dioxygenase-catalyzed reaction [106]. Another reducing agent ascorbate accelerates enzymatic reactions, which are catalyzed by Fe 2+ -2-oxoglutaratedependent family of dioxygenases [107].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Superoxide Signaling in Epigenetic Processes: Relation to Aging and Cancer

Afanas’ev¹

2015

Aging and disease

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Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems. It has been shown that superoxide regulates major epigenetic processes of DNA methylation, histone methylation, and histone acetylation. We suggested that superoxide, being a radical anion and a strong nucleophile, could participate in DNA methylation and histone methylation and acetylation through mechanism of nucleophilic substitution and free radical abstraction. In nucleophilic reactions superoxide is able to neutralize positive charges of methyl donors S-adenosyl-L-methionine (SAM) and acetyl-coenzyme A (AcCoA) enhancing their nucleophilic capacity or to deprotonate cytosine. In the reversed free radical reactions of demethylation and deacetylation superoxide is formed catalytically by the (Tet) family of dioxygenates and converted into the iron form of hydroxyl radical with subsequent oxidation and final eradication of methyl substituents. Double role of superoxide in these epigenetic processes might be of importance for understanding of ROS effects under physiological and pathological conditions including cancer and aging.

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“…Nevertheless, initial biochemical studies did not support this contention; reducing agents other than ascorbate were apparently insufficient to enhance TET activity in vitro [45,50,51,53]. Subsequent cell culture experiments using quinones as reducing agents [54,55], and further in vitro experiments at physiological pH [37] have now challenged this conclusion. Ascorbate has been found not to enhance TET activity when in the presence of sufficient Fe 2+ , demonstrating it is not an obligatory cofactor [37].…”

Section: Vitamin a Enhances Tet Expression Vitamin C Potentiates Tetmentioning

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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Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism

Cited by 109 publications

References 59 publications

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Mechanisms of Superoxide Signaling in Epigenetic Processes: Relation to Aging and Cancer

Modulating epigenetic memory through vitamins and TET: implications for regenerative medicine and cancer treatment

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