Journal
CELL REPORTS
Volume 7, Issue 5, Pages 1343-1352Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.04.040
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Funding
- NIH [T32-HD007009-38, P01-HL090554-06]
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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 a-ketoglutarate. Given that the TET enzymes also require these cofactors, we hypothesized that the TETs regulate the hypoxiainduced 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.
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