Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

By Mamta Tahiliani, Kian Peng Koh, Yinghua Shen, William A. Pastor, Hozefa S. Bandukwala, Y. Brudno, Suneet Agarwal, Lakshminarayan M. Iyer, David R. Liu, L. Aravind and 1 more. Science, 2009

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Methylation Mediation Methylation of cytosine bases, 5-methylcytosine (5mC), in DNA plays an important regulatory role in mammalian genomes. Methylation patterns are often inherited across generations, but they can also be dynamic, suggesting that active DNA demethylation pathways exist. One such pathway, best characterized in plants, involves the removal of the 5mC base, and its replacement by C, via a DNA repair mechanism. Kriaucionis and Heintz (p. 929, published online 16 April) now show that, as well as 5mC in mammalian genomes, there are also significant amounts of 5-hydroxymethylcytosine (5hmC) in DNA of Purkinje neurons, which have large nuclei with apparently very little heterochromatin. Tahiliani et al. (p. 930, published online 16 April) find that the protein TET1 is capable of converting 5mC into 5hmC both in vitro and in vivo. 5-Hydroxymethylcytosine is also present in embryonic stem cells, and levels of 5hmC and TET1 show correlated variation during cell differentiation. Methylated C bases, an important epigenetic mark in genomic DNA, can be enzymically converted to 5-hydroxymethylcytosine. DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3d7c175818c55ddcc0bb9937329fa3c2779eeb62

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Citations in the corpus

Epigenetic modifications and human disease (2010, background): “, the report of new epigenetic machinery such as the DNA demethylase Tet1 (refs”
Influence of Metabolism on Epigenetics and Disease (2013, positive): “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).”
Lessons from the cancer genome. (2013, neutral): “In 2009, biochemical studies identified a new type of DNA modification: the conversion of 5-methylcytosine (5mC) at CpG islands to a hydroxylated variant called 5-hydroxymethylcytosine (5hmC) by the ten/ eleven translocation (TET) family of DNA hydroxylases (Kriaucionis and Heintz, 2009; Tahiliani e”
Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence (2014, neutral): “Ten-eleven translocation (Tet) dioxygenases then convert a fraction of these to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5carboxylcytosine (5caC) in consecutive oxidation reactions (Kriaucionis and Heintz 2009; Tahiliani et al. 2009; Globisch et al. 2010; Ito et al. 2010, 2011; He”
Early detection of cancer (2022, neutral): “These include cancer-specific DNA methylation profiles (68), noncoding RNAs (69), small regulatory RNAs, and the DNA modification 5-hydroxymethylcytosine (70).”
Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, positive): “This observation is corroborated in mouse ESCs (Figure S2H–I), and is consistent with a previous estimate of global 5hmC levels in embryonic stem cells (Tahiliani et al., 2009).”
DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, result): “In contrast to early data suggesting a 16-h cell cycle in PGCs (Tam and Snow 1981) recent BrdU pulse-chase experiments describe faster (;12 h per cycle), exponential proliferation until at least E12.”
Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair (2011, neutral): “Recently, 5-hydroxymethylcytosine (5hmC), an oxidative product of 5mC generated by the Tet hydroxylases (Kriaucionis and Heintz, 2009; Tahiliani et al., 2009), has been proposed as a demethylation intermediate (Globisch et al.”
ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “DHSs have been used as markers of regulatory DNA regions [35,36] including promoters, enhancers, insulators, silencers, and locus control regions.”