TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma

Cell Rep. 2014 Jun 12;7(5):1343-1352. doi: 10.1016/j.celrep.2014.04.040. Epub 2014 May 15.


The ten-eleven-translocation 5-methylcytosine dioxygenase (TET) family of enzymes catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), a modified cytosine base that facilitates gene expression. Cells respond to hypoxia by inducing a transcriptional program regulated in part by oxygen-dependent dioxygenases that require Fe(II) and α-ketoglutarate. Given that the TET enzymes also require these cofactors, we hypothesized that the TETs regulate the hypoxia-induced transcriptional program. Here, we demonstrate that hypoxia increases global 5-hmC levels, with accumulation of 5-hmC density at canonical hypoxia response genes. A subset of 5-hmC gains colocalize with hypoxia response elements facilitating DNA demethylation and HIF binding. Hypoxia results in transcriptional activation of TET1, and full induction of hypoxia-responsive genes and global 5-hmC increases require TET1. Finally, we show that 5-hmC increases and TET1 upregulation in hypoxia are HIF-1 dependent. These findings establish TET1-mediated 5-hmC changes as an important epigenetic component of the hypoxic response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cytosine / analogs & derivatives
  • Cytosine / metabolism
  • DNA Methylation*
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mixed Function Oxygenases
  • Neuroblastoma / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Response Elements
  • Up-Regulation


  • DNA-Binding Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Mixed Function Oxygenases
  • TET1 protein, human

Associated data

  • GEO/GSE55391