Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA

He, Yufei; Li, Bin-Zhong; Zheng, Lirong; Liu, Peng; Wang, Yan; Tang, Qingyu; Ding, Jianping; Jia, Yingying; Chen, Zhangcheng; Lin, Li; Sun, Yan; Li, Xiuxue; Dai, Qing; Song, Chun-Xiao; Zhang, Kangling; He, Chuan; Xu, Guoliang

doi:10.1126/science.1210944

Cited by 2,341 publications

(2,228 citation statements)

References 32 publications

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“…With respect to methylation changes, one might speculate that the glycosylase activity of NEIL1, in addition to thymine-DNA glycosylase (TDG), might be implicated in the teneleven translocation (TET)-mediated and base excision repair (BER)-coupled demethylation pathways which involve oxidized products of 5-mC such as 5-hydroxymethylcytosine or 5-carboxylcytosine. 41 An impaired demethylating activity could then contribute to increased methylation in tumors.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

et al. 2012

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Aberrant promoter methylation of different DNA repair genes has a critical role in the development and progression of various cancer types, including head and neck squamous cell carcinomas (HNSCCs). A systematic analysis of known human repair genes for promoter methylation is however missing. We generated quantitative promoter methylation profiles in single CpG units of 160 human DNA repair genes in a set of DNAs isolated from fresh frozen HNSCC and normal tissues using MassARRAY technology. Ninety-eight percent of these genes contained CpG islands (CGIs) in their promoter region; thus, DNA methylation is a potential regulatory mechanism. Methylation data were obtained for 145 genes, from which 15 genes exhibited more than a 20% difference in methylation levels between tumor and normal tissues, manifested either as hypermethylation or as hypomethylation. Analyses of promoter methylation with mRNA expression identified the DNA glycosylase NEIL1 (nei endonuclease VIII-like 1) as the most prominent candidate gene. NEIL1 promoter hypermethylation was confirmed in additional fresh frozen HNSCC samples, normal mucosa, HNSCC cell lines and primary human skin keratinocytes. The investigation of laser-microdissected tissues further substantiated increased methylation levels in tumor versus matched non-tumor cells. Immunohistological analysis revealed significantly less NEIL1 protein expression in tumor tissues. 5-Aza-2 0 -deoxycytidine treatment and DNMT1 knockdown resulted in the re-expression of NEIL1 in HNSCC cell lines, which initially carried hypermethylated promoter regions. In conclusion, our results suggest that DNA methylation contributes to the downregulation of NEIL1 expression and might thus have a role in modulating the response to therapies of HNSCC.

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Section: Discussionmentioning

confidence: 99%

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

et al. 2012

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“…Tet proteins (Tet1, Tet2, and Tet3) are Fe 2+ -dependent and 2-oxoglutarate-dependent dioxygenases that oxidize 5-methylcytosines (5mC) into intermediates, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (32)(33)(34), which would eventually be replaced with unmethylated cytosine (35). Recently, we demonstrated that the overexpression of Tet2 restored CNS2 demethylation in Il2 2/2 tTregs, implying that the upregulation of Tet2 participates in CNS2 demethylation (36).…”

Section: Vitamin C Facilitates Demethylation Of the Foxp3 Enhancer Inmentioning

confidence: 99%

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

Nair

Song

2016

The Journal of Immunology

144

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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.

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“…DNA methylation is generally thought to be relatively stable and heritable. This view is recently changed by the discovery of TET (ten-eleven translocation) family of dioxygenases which catalyze three sequential oxidation reactions: converting 5mC first to 5hmC, and then 5-formylcytosine (5fC), and finally 5-carboxylcytosine (5caC) [3][4][5][6][7]. A subsequent decarboxylation of 5caC could then lead to DNA demethylation [3].…”

Section: Dear Editormentioning

confidence: 99%

TET-catalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites

Yang

Lin

et al. 2014

Cell Res

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Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA

Cited by 2,341 publications

References 32 publications

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

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

TET-catalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites

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