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Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

ABSTRACT: 5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.

SUBMITTER: Ito S

PROVIDER: S-EPMC3495246 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

Ito Shinsuke S Shen Li L Dai Qing Q Wu Susan C SC Collins Leonard B LB Swenberg James A JA He Chuan C Zhang Yi Y

Science (New York, N.Y.) 20110721 6047

5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic ...[more]

PMID: 21778364

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Project description:BACKGROUND:Prognostic tools for prostate cancer (PC) are inadequate and new molecular biomarkers may improve risk stratification. The epigenetic mark 5-hydroxymethylcytosine (5hmC) has recently been proposed as a novel candidate prognostic biomarker in several malignancies including PC. 5hmC is an oxidized derivative of 5-methylcytosine (5mC) and can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The present study is the first to investigate the biomarker potential in PC for all four DNA methylation marks in parallel. Thus, we determined 5mC, 5hmC, 5fC, and 5caC levels in non-malignant (NM) and PC tissue samples from a large radical prostatectomy (RP) patient cohort (n?=?546) by immunohistochemical (IHC) analysis of serial sections of a tissue microarray. Possible associations between methylation marks, routine clinicopathological parameters, ERG status, and biochemical recurrence (BCR) after RP were investigated. RESULTS:5mC and 5hmC levels were significantly reduced in PC compared to NM prostate tissue samples (p ? 0.027) due to a global loss of both marks specifically in ERG- PCs. 5fC levels were significantly increased in ERG+ PCs (p?=?0.004), whereas 5caC levels were elevated in both ERG- and ERG+ PCs compared with NM prostate tissue samples (p ? 0.019). Positive correlations were observed between 5mC, 5fC, and 5caC levels in both NM and PC tissues (p?<?0.001), while 5hmC levels were only weakly positively correlated to 5mC in the PC subset (p?=?0.030). There were no significant associations between 5mC, 5fC, or ERG status and time to BCR in this RP cohort. In contrast, high 5hmC levels were associated with BCR in ERG- PCs (p?=?0.043), while high 5caC levels were associated with favorable prognosis in ERG+ PCs (p?=?0.011) and were borderline significantly associated with worse prognosis in ERG- PCs (p?=?0.058). Moreover, a combined high-5hmC/high-5caC score was a significant adverse predictor of post-operative BCR beyond routine clinicopathological variables in ERG- PCs (hazard ratio 3.18 (1.54-6.56), p?=?0.002, multivariate Cox regression). CONCLUSIONS:This is the first comprehensive study of 5mC, 5hmC, 5fC, and 5caC levels in PC and the first report of a significant prognostic potential for 5caC in PC.

Dataset Information

Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

Publications

Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

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