Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation

Wu, Hao; Zhang, Yi

doi:10.1101/gad.179184.111

Cited by 587 publications

(517 citation statements)

References 121 publications

(211 reference statements)

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“…It is well known that one of the major functions of DNA methylation is to maintain genome integrity through suppressing the expression of TEs [14,32]. Given that Tet3-mediated 5mC oxidation is part of the DNA demethylation mechanism [8], the results described above are surprising. Then, how is TE expression activated in early preimplantation embryos?…”

Section: Tet3-mediated 5mc Oxidation Is Dispensable For Zygotic Gene contrasting

confidence: 48%

“…Although this dynamic event was reported a decade ago, the molecular mechanism as well as its biological significance just begin to be revealed. The discovery that the ten-eleven translocation (Tet) family of proteins have the capacity to oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) [3,4], 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) [5,6] in combination with the fact that the glycosylase Tdg can remove 5fC and 5caC [5,7] suggest a mechanism by which 5mC can be removed through the coordinated action of Tet and Tdg proteins followed by DNA repair [8]. Consistently, loss of 5mC in paternal genome in the zygotes correlates with Tet3-mediated 5mC oxidation [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

2012

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The methylation state of the paternal genome is rapidly reprogrammed shortly after fertilization. Recent studies have revealed that loss of 5-methylcytosine (5mC) in zygotes correlates with appearance of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). This process is mediated by Tet3 and the 5mC oxidation products generated in zygotes are gradually lost during preimplantation development through a replicationdependent dilution process. Despite these findings, the biological significance of Tet3-mediated oxidation of 5mC to 5hmC/5fC/5caC in zygotes is unknown. DNA methylation plays an important role in silencing gene expression including the repression of transposable elements (TEs). Given that the activation of TEs during preimplantation development correlates with loss of DNA methylation, it is believed that paternal DNA demethylation may have an important role in TE activation. Here we examined this hypothesis and found that Tet3-mediated 5mC oxidation does not have a significant contribution to TE activation. We show that the expression of LINE-1 (long interspersed nucleotide element 1) and ERVL (endogenous retroviruses class III) are activated from both paternal and maternal genomes in zygotes. Inhibition of 5mC oxidation by siRNA-mediated depletion of Tet3 affected neither TE activation, nor global transcription in zygotes. Thus, our study provides the first evidence demonstrating that activation of both TEs and global transcription in zygotes are independent of Tet3-mediated 5mC oxidation.

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Section: Tet3-mediated 5mc Oxidation Is Dispensable For Zygotic Gene contrasting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

2012

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“…LNCaP, BicR, 22Rv1 and LTAD (3 Â 10 6 ) cells were subcutaneously injected into each side of twenty 5-week-old male BALB/C nude mice. For the experiment of LNcaP and BicR xenografts, the mice were randomly divided into three groups when the tumour volumes reached 100 mm 3 . Each group was treated with vehicle or bicalutamide (20 mg kg À 1 ; Santa Cruz Biotechnology) orally every other day and an intratumoral injection of antimiRNA-29b was started.…”

Section: Methodsmentioning

confidence: 99%

“…The resultant regulation of gene expression is thought to govern various biological phenomena, including cancer progression. 5-Hydroxymethylation of cytosine bases (5-hmC) is a newly identified epigenetic marker; this nontraditional DNA modification involves methylation of cytosine bases (5-mC) in CpG dinucleotide sequences 2,3 and their oxidation by the ten-eleven translocation (TET) family of proteins. While 5-hmC is a potentially useful indicator of disease states such as cancer [4][5][6][7][8] , the mechanisms controlling its abundance in tumours and its impact on gene expression and cancer cell fate are unclear.…”

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confidence: 99%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

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“…Since the CD domains of Tet proteins are conserved, 12,13 these results indicate that AA may directly interact with the CD domain of Tet proteins to enhance 5mC oxidation.…”

Section: ■ Introductionmentioning

confidence: 91%

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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Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation

Cited by 587 publications

References 121 publications

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

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

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