TET enzymes, TDG and the dynamics of DNA demethylation

Kohli, Rahul M.; Zhang, Yi

doi:10.1038/nature12750

Cited by 1,381 publications

(1,125 citation statements)

References 104 publications

(162 reference statements)

Supporting

Mentioning

1,101

Contrasting

Unclassified

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Active DNA demethylation involves oxidation reactions of 5mC into oxidized methylcytosines, such as 5hmC, 5fC and 5caC. Eventually, the oxidized methylcytosines are replaced with unmodified cytosine in various ways, including passive dilution and base excision repair (35,48,49). To investigate the underlying mechanisms of CNS2 demethylation induced by vitamin C, we checked cell proliferation by using flow cytometry.…”

Section: Vitamin C Induced Cns2 Demethylation In Itregsmentioning

confidence: 99%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

View full text Add to dashboard Cite

Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

show abstract

“…Ten-eleven translocation (TET) proteins (Kohli and Zhang 2013) and the enzyme, DNA methyltransferase (DNMT) (Jaenisch and Bird 2003;Goll and Bestor 2005), have an important role in regulating DNA methylation. Specifically, TET proteins mediate the hydroxymethylation of DNA, whereas DNMT is responsible for DNA methylation (Gavin et al, 2013).…”

Section: Dexamethasone Modulates Methylation and Hydroxymethylation Mmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

show abstract

TET enzymes, TDG and the dynamics of DNA demethylation

Cited by 1,381 publications

References 104 publications

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

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

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Contact Info

Product

Resources

About