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.
Tahiliani
Mamta
M
Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
Koh
Kian Peng
KP
Shen
Yinghua
Y
Pastor
William A
WA
Bandukwala
Hozefa
H
Brudno
Yevgeny
Y
Agarwal
Suneet
S
Iyer
Lakshminarayan M
LM
Liu
David R
DR
Aravind
L
L
Rao
Anjana
A
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