Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

Science. 2009 May 15;324(5929):930-5. doi: 10.1126/science.1170116. Epub 2009 Apr 16.

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