Direct decarboxylation of ten-eleven translocation-produced 5-carboxylcytosine in mammalian genomes forms a new mechanism for active DNA demethylation

Yang, Feng; Chen, Juanjuan; Xie, Neng-Bin; Ding, Jiang-Hui; You, Xue-Jiao; Tao, Wan-Bing; Zhang, Xiaoxue; Yi, Chengqi; Zhou, Xiang; Yuan, Bi-Feng; Feng, Yu‐Qi

doi:10.1039/d1sc02161c

Cited by 31 publications

(28 citation statements)

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“…5 The resulting 5fC and 5caC undergo base excision repair or direct deformylation or decarboxylation to restore unmodied cytosines. [5][6][7][8][9] The discovery of 5hmC in mammalian genomes is a landmark in epigenomics study. 10 Similar to 5mC in DNA, 5hmC is also viewed as a vital epigenetic marker that could modulate gene expression.…”

Section: Introductionmentioning

confidence: 99%

Bisulfite-free and single-nucleotide resolution sequencing of DNA epigenetic modification of 5-hydroxymethylcytosine using engineered deaminase

Xie

Wang

et al. 2022

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

Bisulfite-free and single-nucleotide resolution sequencing of DNA epigenetic modification of 5-hydroxymethylcytosine using engineered deaminase

Xie

Wang

et al. 2022

Chem. Sci.

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“…0.0004%) are low, they fall within a similar range to those determined in different mammalian tissues (0.00004–0.0005%; [ 6 ]) ( figure 1 d ). The relatively weak TET activity towards 5caC generation, as reported by in vitro analysis of C. cinerea TET proteins on DNA [ 71 ], might be responsible for the lowest amounts of 5carC among all oxi-mCs, or 5caC might be actively removed from DNA and RNA by excision mechanisms, such as thymine DNA glycosylases or direct decarboxylation to cytosine [ 72 ]. However, to date, the activity of thymine DNA glycosylases (a potential gene was predicted in C. cinerea ; [ 29 ]) or other excision mechanisms have not yet been discovered in fungi.…”

Section: Discussionmentioning

confidence: 99%

Distribution and regulatory roles of oxidized 5-methylcytosines in DNA and RNA of the basidiomycete fungi Laccaria bicolor and Coprinopsis cinerea

et al. 2022

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The formation of three oxidative DNA 5-methylcytosine (5mC) modifications (oxi-mCs)—5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)—by the TET/JBP family of dioxygenases prompted intensive studies of their functional roles in mammalian cells. However, the functional interplay of these less abundant modified nucleotides in other eukaryotic lineages remains poorly understood. We carried out a systematic study of the content and distribution of oxi-mCs in the DNA and RNA of the basidiomycetes Laccaria bicolor and Coprinopsis cinerea, which are established models to study DNA methylation and developmental and symbiotic processes. Quantitative liquid chromatography–tandem mass spectrometry revealed persistent but uneven occurrences of 5hmC, 5fC and 5caC in the DNA and RNA of the two organisms, which could be upregulated by vitamin C. 5caC in RNA (5carC) was predominantly found in non-ribosomal RNA, which potentially includes non-coding, messenger and small RNA species. Genome-wide mapping of 5hmC and 5fC using the single CG analysis techniques hmTOP-seq and foTOP-seq pointed at involvement of oxi-mCs in the regulation of gene expression and silencing of transposable elements. The implicated diverse roles of 5mC and oxi-mCs in the two fungi highlight the epigenetic importance of the latter modifications, which are often neglected in standard whole-genome bisulfite analyses.

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“…Without clear identification of the biological entity responsible for the process, we cannot completely rule out that unknown processes other than intragenomic decarboxylation are responsible for the measured data. During the review process of this manuscript Feng and co‐workers showed an incorporation of the F‐carboxycytosine as a nucleoside and interestingly managed to detect the decarboxylation of cadC to dC much earlier on [29] …”

Section: Figurementioning

confidence: 99%

“…During the review process of this manuscript Feng and co‐workers showed an incorporation of the F‐carboxycytosine as a nucleoside and interestingly managed to detect the decarboxylation of cadC to dC much earlier on. [29] …”

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Intragenomic Decarboxylation of 5‐Carboxy‐2′‐deoxycytidine

et al. 2021

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Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present. The methylation of dC to mdC is known to regulate transcriptional activity. Next to these five nucleosides, the genome, particularly of stem cells, contains three additional dC derivatives, which are formed by stepwise oxidation of the methyl group of mdC with the help of Tet enzymes. These are 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC), and 5carboxy-dC (cadC). It is believed that fdC and cadC are converted back into dC, which establishes an epigenetic control cycle that starts with methylation of dC to mdC, followed by oxidation and removal of fdC and cadC. While fdC was shown to undergo intragenomic deformylation to give dC directly, a similar decarboxylation of cadC was postulated but not yet observed on the genomic level. By using metabolic labelling, we show here that cadC decarboxylates in several cell types, which confirms that both fdC and cadC are nucleosides that are directly converted back to dC within the genome by CÀC bond cleavage.

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Direct decarboxylation of ten-eleven translocation-produced 5-carboxylcytosine in mammalian genomes forms a new mechanism for active DNA demethylation

Abstract: DNA cytosine methylation (5-methylcytosine, 5mC) is the most important epigenetic mark in higher eukaryotes. 5mC in genomes is dynamically controlled by the writers and erasers. DNA (cytosine-5)-methyltransferases (DNMTs) are responsible...

Cited by 31 publications

References 37 publications

Bisulfite-free and single-nucleotide resolution sequencing of DNA epigenetic modification of 5-hydroxymethylcytosine using engineered deaminase

Bisulfite-free and single-nucleotide resolution sequencing of DNA epigenetic modification of 5-hydroxymethylcytosine using engineered deaminase

Distribution and regulatory roles of oxidized 5-methylcytosines in DNA and RNA of the basidiomycete fungi Laccaria bicolor and Coprinopsis cinerea

Intragenomic Decarboxylation of 5‐Carboxy‐2′‐deoxycytidine

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