Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.
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.
Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
Mamta
M
Tahiliani
Kian Peng
KP
Koh
Yinghua
Y
Shen
William A
WA
Pastor
Hozefa
H
Bandukwala
Yevgeny
Y
Brudno
Suneet
S
Agarwal
Lakshminarayan M
LM
Iyer
David R
DR
Liu
L
L
Aravind
Anjana
A
Rao
D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D013058:Mass Spectrometry; D051379:Mice; D006899:Mixed Function Oxygenases; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016415:Sequence Alignment; D014162:Transfection
D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D006899:Mixed Function Oxygenases; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; C015772:CpG dinucleotide; C462539:TET1 protein, human