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Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.

Cell | Apr 29, 2011

Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals.

Pubmed ID: 21496894 RIS Download

Mesh terms: 5-Methylcytosine | Adult | Animals | Base Sequence | Brain | Cytidine Deaminase | DNA Methylation | DNA Repair | DNA-Binding Proteins | Humans | Hydroxylation | Mixed Function Oxygenases | Proto-Oncogene Proteins

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Associated grants

  • Agency: NICHD NIH HHS, Id: R01 HD069184
  • Agency: NICHD NIH HHS, Id: R01 HD069184-01
  • Agency: NINDS NIH HHS, Id: R01 NS048271-06
  • Agency: NIMH NIH HHS, Id: R21 MH087874
  • Agency: NIA NIH HHS, Id: R01 AG024984
  • Agency: NIA NIH HHS, Id: AG024984
  • Agency: NIMH NIH HHS, Id: R33 MH087874
  • Agency: NINDS NIH HHS, Id: NS048271
  • Agency: NINDS NIH HHS, Id: R37 NS047344
  • Agency: NIMH NIH HHS, Id: MH087874
  • Agency: NINDS NIH HHS, Id: R56 NS047344
  • Agency: NINDS NIH HHS, Id: R01 NS047344-09
  • Agency: NINDS NIH HHS, Id: R01 NS048271
  • Agency: NINDS NIH HHS, Id: R01 NS047344
  • Agency: NICHD NIH HHS, Id: HD069184
  • Agency: NINDS NIH HHS, Id: NS047344
  • Agency: NIA NIH HHS, Id: R01 AG024984-05

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