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

By Shinsuke Ito, Li Shen, Qing Dai, Susan C. Wu, L. Collins, J. Swenberg, Chuan He, Yi Zhang. Science, 2011

3,315 citations recorded by the source corpus.

Evidence for a possible route for DNA demethylation in animals is suggested. 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/42af3a963e9212d43d2721b7479a4821d008bb5b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Yi Zhang
2. Hao Wu
3. K. Guan
4. Xiu-Jie Wang
5. E. Nestler
6. Chuan He
7. K. Helin
8. Peng Jin

In Molecular Biology

1. Yi Zhang
2. Hao Wu
3. Chuan He
4. Craig B. Thompson
5. K. Helin
6. Brian D. Strahl
7. Scott B. Rothbart
8. Chao Lu

Citations in the corpus

• Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “Although the amount of 5hmC in the genome is dependent on levels of TET activity, steady-state levels of 5hmC will also depend on activities that further modify 5hm”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “01% of 5mC) (Ito et al., 2011; Pfaffeneder et al., 2011), suggesting that TET enzymes tend to stall at 5hmC.”
• Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence (2014, neutral): “…(Tet) dioxygenases then convert a fraction of these to 5-hydroxy-methylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in consecutive oxidation reactions (Kriaucionis and Heintz 2009; Tahiliani et al. 2009; Globisch et al. 2010; Ito et al. 2010, 2011; He et al. 2011).”
• Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “6-fold) substrates compared with the initial oxidation reaction of 5mC (Ito et al. 2011; Hu et al. 2015).”
• Metabolic regulation of epigenetics (2012, background): “The only difference is that in this reaction, the hydroxymethyl group is a stable product and further TET-dependent modification is undertaken with low stoichiometry (He et al., 2011; Ito et al., 2011).”
• Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, positive): “In addition, 5hmC can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by TET proteins (He et al., 2011; Ito et al., 2011; Pfaffeneder et al., 2011), and demethylation pathways through these modified cytosines have been shown (Cortellino et al.”
• Clonal hematopoiesis in human aging and disease (2019, neutral): “TET2 is one of three enzymes responsible for catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and further intermediates, which can eventually lead to demethylation (49, 50).”
• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, methodology): “The robust excision activity of TDG toward 5fC and 5caC may be one explanation as to why 5fC and 5caC are present at very low levels in the genome compared with 5hmC (Ito et al. 2011; Pfaffeneder et al. 2011).”
• Influence of Metabolism on Epigenetics and Disease (2013, neutral): “TET proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxylcytosine (5caC) (He et al., 2011; Ito et al., 2011; Tahiliani et al., 2009).”
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “5fC and 5caC are present low abundance in mammalian genomes [54] and are difficult to be detected by ChIP-seq.”
• DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, neutral): “2B; He et al. 2011; Inoue et al. 2011; Ito et al. 2011).”