Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells

Huang, Yun; Chávez, Lukas; Chang, Xing; Wang, Xue; Pastor, William A.; Kang, Jinsuk; Zepeda-Martínez, Jorge A.; Pape, Utz Johann; Jacobsen, Steven E.; Peters, Bjoern; Rao, Anjana

doi:10.1073/pnas.1322921111

Cited by 226 publications

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“…5hmC enrichment over the gene body of highly expressed genes has also been noted in mouse ES cells (30), neuronal cells/ tissues (29), and differentiating sperm cells (44) (reviewed in ref. 9).…”

Section: Discussionmentioning

confidence: 98%

“…5hmC is a particularly stable and abundant mark, comprising ∼5-10, 40, and ∼1% of total 5mC in ES cells, Purkinje neurons, and immune cells, respectively (47,51). In consequence, the relation between 5mC and 5hmC is not a simple one: 5mC is a substrate for 5hmC, but any single TET protein contributes only partially to the generation of 5hmC (30), and the existence of three distinct oxi-mC modifications adds to the complex relationship of 5mC to oxi-mC (reviewed in ref. 9).…”

Section: Discussionmentioning

confidence: 99%

“…5hmC was particularly enriched in gene bodies of the most highly expressed genes [reads per kilobase per million mapped reads (RPKM) > 100, Fig. 1C], reminiscent of its distribution in neurons (29) and in embryonic stem (ES) cells (27,30). The correlation remained strong even when all genes-both expressed and nonexpressedwere considered ( Fig.…”

Section: Capturing 5hmc Distribution In Different T-cell Subsets Duringmentioning

confidence: 94%

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Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Tsagaratou

Äijö

Lio

et al. 2014

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

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The discovery of Ten Eleven Translocation proteins, enzymes that oxidize 5-methylcytosine (5mC) in DNA, has revealed novel mechanisms for the regulation of DNA methylation. We have mapped 5-hydroxymethylcytosine (5hmC) at different stages of T-cell development in the thymus and T-cell differentiation in the periphery. We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression. Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect. Our data constitute a valuable resource that will facilitate detailed analysis of the role of 5hmC in T-cell development and differentiation.thymic development | epigenetics

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Capturing 5hmc Distribution In Different T-cell Subsets Duringmentioning

confidence: 94%

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Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Tsagaratou

Äijö

Lio

et al. 2014

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

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“…We show that oxi-mCs mark TET/JBP transposons and other repetitive elements in C. cinerea, and are also enriched at centromeres. There is an overall correlation between the distribution of 5mC and oxi-mC in C. cinerea, as in mammals (24); however, whereas 5hmC is enriched in the gene bodies of highly expressed genes in mammals (14,25,26), oxi-mC modifications mark genes that are silent or poorly expressed in C. cinerea, and tend to be excluded from highly expressed genes and genes whose expression is altered between oidia (haploid spores) and haploid mycelia.…”

mentioning

confidence: 97%

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

Chávez

Huang

Luong

et al. 2014

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

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TET/JBP enzymes oxidize 5-methylpyrimidines in DNA. In mammals, the oxidized methylcytosines (oxi-mCs) function as epigenetic marks and likely intermediates in DNA demethylation. Here we present a method based on diglucosylation of 5-hydroxymethylcytosine (5hmC) to simultaneously map 5hmC, 5-formylcytosine, and 5-carboxylcytosine at near-base-pair resolution. We have used the method to map the distribution of oxi-mC across the genome of Coprinopsis cinerea, a basidiomycete that encodes 47 TET/JBP paralogs in a previously unidentified class of DNA transposons. Like 5-methylcytosine residues from which they are derived, oxi-mC modifications are enriched at centromeres, TET/JBP transposons, and multicopy paralogous genes that are not expressed, but rarely mark genes whose expression changes between two developmental stages. Our study provides evidence for the emergence of an epigenetic regulatory system through recruitment of selfish elements in a eukaryotic lineage, and describes a method to map all three different species of oxi-mCs simultaneously.T he discovery that oxidative modifications of DNA bases are catalyzed by the TET/JBP family of 2-oxoglutarate and irondependent dioxygenases (1-4) opened a major area of research into the epigenetics of various eukaryotic lineages (reviewed in refs. 5-7). In metazoans, the TET/JBP family is represented by TET proteins, which are present in all animals that are known to possess DNA cytosine methylation (3,8,9). The three TET paralogs of vertebrates have been shown to catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (2), which is progressively oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (10-12). The discovery of these oxidized methylcytosine (oxi-mC) modifications triggered a flurry of studies on the mammalian TET paralogs; the reports increasingly point toward important roles for these oxidative modifications as intermediates in the enigmatic process of DNA demethylation, and also as epigenetic marks in their own right (13, 14) (reviewed in refs. 5-7). TET proteins have roles in diverse biological processes, including epigenetic regulation of gene transcription, embryonic development, stem cell function, and cancer (5), but the mechanisms underlying their biological activities are still poorly defined.Several methods have been developed to profile individual oxi-mC species at base resolution in genomic DNA (reviewed in ref. 5). However, none of these methods can simultaneously map all three oxi-mC species-5hmC, 5fC, and 5caC-at the same time; rather, they rely on chemical or enzymatic conversion of individual oxi-mCs followed by bisulfite sequencing. Two recent sequencing technologies, single-molecule, real-time (SMRT) sequencing and protein nanopore sequencing, are capable of recognizing modified bases in unamplified genomic DNA (15-18). In SMRT sequencing, 5mC and 5hmC are barely detectable in unmodified DNA, whereas 5fC and 5caC yield a robust kinetic signature (16). As 5hmC is an abundant oxi-mC modification in ...

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“…TET1 se fixe au niveau des régions d'initiation de la transcription (TSS) enrichies en CpG et, à un degré moindre, dans le corps des gènes [7,9]. La fixation de TET2, malgré un certain chevauchement avec les sites de fixation de TET1, prédomine dans le corps des gènes qui sont activement transcrits [10]. Ces sites de fixation se trouvent dans des régions où puis une endonucléase apurinique/apyrimidique (APE1) excise le nucléotide.…”

Section: Rôle Activateur De La Transcription Via Les 5-hydroxyméthylcunclassified

Propriétés et rôles biologiques des protéines TET au cours du développement et de l’hématopoïèse

et al. 2015

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> La méthylation de l'ADN est associée à de nombreux processus biologiques et concerne la méthylation de la cytosine en position 5 (5-mC). Un mécanisme actif de déméthylation, jusqu'alors discuté, a été mis en évidence en 2009 à la suite de la découverte des protéines TET (ten-eleven-translocation). Ces protéines sont des enzymes capables d'hydroxyler la 5-mC en 5-hydroxyméthylcytosine. Simultanément, d'autres études ont montré la fréquence et le rôle des mutations acquises de TET2 dans les hémopathies et leur pathogenèse. Depuis, ces protéines ont été impliquées dans de très nombreux processus, ouvrant un nouveau domaine de recherche. Dans cette revue, nous discuterons les fonctions enzymatique et biologique de ces protéines, ainsi que leurs rôles, notamment au cours de l'hématopoïèse et du développement. < fixe aux 5-mC grâce à trois atomes de zinc, qui sont coordonnés par les domaines riches en cystéine et le domaine DSBH [2]. Fonction enzymatique des TETLes enzymes TET sont impliquées dans la première étape d'un processus de déméthylation actif qui se termine par le remplacement par une cytosine non méthylée. Elles sont capables d'initier ce processus en hydroxylant les 5-mC en 5-hydroxyméthylcytosines (5-hmC) (Figure 2) [3]. Les 5-hmC ont été principalement identifiées dans les cellules souches embryonnaires (CSE) et les neurones adultes, où elles repré-sentent 15 à 40 % des 5-mC ; elles sont aussi présentes dans tous les types cellulaires, mais n'y constituent que 1 à 5 % des 5-mC [3,4]. Il y a ensuite deux voies de transformation des 5-hmC :• Les 5-hmC peuvent être déaminées par des cytidine déaminases de la famille AID/APOBEC (activation-induced cytidine deaminase / apolipoprotein B mRNA editing enzyme, catalytic polypeptide like) pour générer les 5-hydroxyméthyluraciles (5-hmU). Des enzymes impliquées dans les mécanismes de réparation de l'ADN par excision de base (BER) sont ensuite utilisées pour la resynthèse de la cytosine non méthylée. Ainsi, les 5-hmU sont reconnues par la thymidine ADN glycosylase (TDG), en association ou pas avec la methyl-binding protein 4 (MBD4),

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Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells

Cited by 226 publications

References 50 publications

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

Propriétés et rôles biologiques des protéines TET au cours du développement et de l’hématopoïèse

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