Abstract
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.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
- 5-Methylcytosine / metabolism*
- Amino Acid Sequence
- Animals
- Cell Line
- Cytosine / analogs & derivatives*
- Cytosine / analysis
- Cytosine / metabolism
- DNA / chemistry
- DNA / metabolism*
- DNA Methylation
- DNA-Binding Proteins / chemistry
- DNA-Binding Proteins / genetics
- DNA-Binding Proteins / metabolism*
- Dinucleoside Phosphates / metabolism
- Embryonic Stem Cells / chemistry
- Embryonic Stem Cells / metabolism
- Humans
- Hydroxylation
- Mass Spectrometry
- Mice
- Mixed Function Oxygenases
- Molecular Sequence Data
- Proto-Oncogene Proteins / chemistry
- Proto-Oncogene Proteins / genetics
- Proto-Oncogene Proteins / metabolism*
- RNA Interference
- Sequence Alignment
- Transfection
Substances
- DNA-Binding Proteins
- Dinucleoside Phosphates
- Proto-Oncogene Proteins
- TET1 protein, mouse
- 5-hydroxymethylcytosine
- cytidylyl-3'-5'-guanosine
- 5-Methylcytosine
- Cytosine
- DNA
- Mixed Function Oxygenases
- TET1 protein, human