The Histone Demethylases Jhdm1a/1b Enhance Somatic Cell Reprogramming in a Vitamin-C-Dependent Manner

Wang, Tao; Chen, Keshi; Zeng, Xiaoming; Yang, Jianguo; Wu, Yun; Shi, Xi; Qin, Baoming; Zeng, Lingwen; Esteban, Miguel A.; Pan, Guangjin; Pei, Duanqing

doi:10.1016/j.stem.2011.10.005

Cited by 418 publications

(388 citation statements)

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“…These results indicate that AA can induce DNA demethylation mainly by enhancing the Tet-mediated oxidation of 5mC. The observation of the slight reduction in 5mC caused by AA in Tet1/Tet2-deleted cells ( Figure 5B) suggests one Tetunrelated but minor mechanism for AA-induced DNA demethylation, which is probably related to histone demethylases 28 AA Regulates a Potential Broad Functional Pathway by 5hmC Formation. To further explore the roles of AA on DNA modifications, we examined the genome-wide distribution and enrichment of 5hmC in mouse ES cells using a selective chemical labeling of 5hmC pull-down approach 33 coupled with deep-sequencing by Illumina HiSeq 2000 platform.…”

Section: ■ Introductionmentioning

confidence: 82%

“…25−29 Limited data suggested that this effect was probably associated with histone demethylases. 28 Since the histone-targeting demethylases cannot directly act on methylated DNA, we speculate that AA should be a better choice to be exploited by Tet dioxygenases to regulate DNA demethylation. The natural choice of nutrient AA would not sacrifice normal cellular functions in mammals.…”

Section: ■ Introductionmentioning

confidence: 97%

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Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

et al. 2013

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DNA hydroxymethylation and its mediated DNA demethylation are critical for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidation of 5-methylcytosine (5mC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidation-resistant derivatives, we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe 2+ . Other strong reducing chemicals do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5mC oxidation products, particularly 5-formylcytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5mC (∼40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5mC oxidation nor the overall level of 5mC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5mC oxidation and DNA demethylation are also observed in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications. ■ INTRODUCTIONDNA demethylation remarkably contributes to the dynamics of the epigenetic marker 5-methylcytosine (5mC) in mammals and is critical for multiple biological processes, including animal cloning, 1 nuclear reprogramming, 2,3 development, 4−8 and highly locus-specific regulation of gene activities. 9−11 DNA demethylation can be initiated by the oxidation of 5mC and the formation of 5-hydroxymethylcytosine (5hmC), which are catalyzed by ten eleven translocation (Tet) family dioxygenases. 12−15 The formed 5hmC can be diluted by DNA replication, suggesting a passive DNA demethylation pathway. 16 Moreover, the 5hmC can be further oxidized by Tet proteins to form 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be excised by thymine DNA glycosylase (TDG) followed by the reintroduction of unmethylated cytosine through the base-excision repair (BER) pathway. 14,15 This important pathway for active DNA demethylation has been thought to be involved in a number of prominent biological processes. 5,6,10,11 Early and recent studies suggested that active and replication-independent DNA demethylation might be a rapid process. 10,11 The radically altered methylation, as observed in replication-independent demethylation of the paternal genome in zygotes, may complete within hours. 5,6,17−19 However, the observed levels of the active DNA demethylation intermediates, 5fC and 5caC in the cultured cells, were 100-fold less than the primary product 5hmC. 13−15,20−22 Biochemically, the Tet-mediated DNA dem...

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Section: ■ Introductionmentioning

confidence: 82%

Section: ■ Introductionmentioning

confidence: 97%

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

et al. 2013

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“…Consistently, it was found that vitamin C can enhance reprogramming in part by reducing p53 expression and alleviating senescence [71]. A recent study further showed that vitamin C promoted reprogramming also by modulating Jhdm1a/1b, two known vitamin Cdependent H3K36 histone demethylases that are potent regulators of reprogramming [72]. Consistently, Jhdm1b activation accelerates cell cycle progression and suppresses cellular senescence by repressing the INK4/ARF locus.…”

Section: Rationale-based Chemical Approachesmentioning

confidence: 73%

Chemical approaches to studying stem cell biology

Jiang

Wei

et al. 2012

Cell Res

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Stem cells, including both pluripotent stem cells and multipotent somatic stem cells, hold great potential for interrogating the mechanisms of tissue development, homeostasis and pathology, and for treating numerous devastating diseases. Establishment of in vitro platforms to faithfully maintain and precisely manipulate stem cell fates is essential to understand the basic mechanisms of stem cell biology, and to translate stem cells into regenerative medicine. Chemical approaches have recently provided a number of small molecules that can be used to control cell selfrenewal, lineage differentiation, reprogramming and regeneration. These chemical modulators have been proven to be versatile tools for probing stem cell biology and manipulating cell fates toward desired outcomes. Ultimately, this strategy is promising to be a new frontier for drug development aimed at endogenous stem cell modulation.

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“…Among the molecules modulating specific signaling pathway or epigenetic state, ascorbic acid (Vitamin C, VC) is a star chemical, which enhanced reprogramming of mouse somatic cells (the human iPSCs culture medium contains VC) (Esteban et al, 2010). The mechanism of VC's function may link to its downstream factor Jhdm1a/1b, a histone demethylase responsible for H3K36me2 or H3K36me3 demethylation which in turn accelerates cell proliferation by repressing the Ink4/Arf locus (Wang et al, 2011). New mouse study from the Hochedlinger group showed that VC attenuated hypermethylation of Dlk1-Dio3 by disenabling intergenic differentially methylated region (IG-DMR) to recruit Dnmt3a (a DNA methyltransferase) in the progress of reprogramming.…”

mentioning

confidence: 99%