Cyclical DNA methylation of a transcriptionally active promoter

Métivier, Raphaël; Gallais, Rozenn; Tiffoche, Christophe; Péron, Christine Le; Jurkowska, Renata Z.; Carmouche, Richard P.; Ibberson, David; Baráth, Péter; Demay, Florence; Reid, George; Beneš, Vladimír; Jeltsch, Albert; Gannon, Frank; Salbert, Gilles

doi:10.1038/nature06544

Cited by 824 publications

(677 citation statements)

References 47 publications

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“…The research to date is also generally consistent with the 'environmental epigenetics' hypothesis, suggesting that environmentally-induced alteration in cell signaling pathways actively remodel DNA methylation states. These findings are also consistent with those of in vitro models, revealing stunningly dynamic regulation of DNA methylation [67,68,[82][83][84]. Although there are a limited range of research models in which this issue has been directly addressed, the evidence in rodents is consistent with the idea that nutritional signals as well as variations in parent-offspring interactions can influence the methylation state of specific genes, which then mediate parental effects on phenotype.…”

Section: Discussionsupporting

confidence: 82%

Environmental regulation of the neural epigenome

et al. 2011

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a b s t r a c tParental effects are a major source of phenotypic plasticity. Moreover, there is evidence from studies with a wide range of species that the relevant parental signals are influenced by the quality of the parental environment. The link between the quality of the environment and the nature of the parental signal is consistent with the idea that parental effects, whether direct or indirect, might serve to influence the phenotype of the offspring in a manner that is consistent with the prevailing environmental demands. In this review we explore recent studies from the field of 'environmental epigenetics' that suggest that (1) DNA methylation states are far more variable than once thought and that, at least within specific regions of the genome, there is evidence for both demethylation and remethylation in post-mitotic cells and (2) that such remodeling of DNA methylation can occur in response to environmentally-driven, intracellular signaling pathways. Thus, studies of variation in mother-offspring interactions in rodents suggest that parental signals operate during pre-and/ or post-natal life to influence the DNA methylation state at specific regions of the genome leading to sustained changes in gene expression and function. We suggest that DNA methylation is a candidate mechanism for parental effects on phenotypic variation.

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Section: Discussionsupporting

confidence: 82%

Environmental regulation of the neural epigenome

et al. 2011

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“…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.…”

Section: ■ Introductionmentioning

confidence: 99%

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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“…Les facteurs épigénétiques étalent leurs effets sur la structure de la chromatine sur des échelles de temps variées allant de la minute, au cours de la signalisation par un récepteur, à des années pour la mémoire métabolique, ou à des générations pour les perturbations environnementales [38,40]. Ainsi, l'ADN subit des cycles de méthylation/ déméthylation indiquant qu'une marque « stable » d'activité génique peut toutefois être modulée par des facteurs de transcription et répondre dynamiquement à des signaux de l'environnement [41]. Contrairement à la séquence génétique, unique et stable dans toutes les cellules, les profils épigénétiques varient d'un type cellulaire à l'autre au sein d'un même tissu, voire même de la partie apicale à la partie distale d'un même tissu.…”

Section: Réversibilité Des Marques Ou Réversibilité Des éTats Phénotyunclassified