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

TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.

Author information

1
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA.
2
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
3
Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
4
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
5
Institute of Physiology and Zurich Center for Human Physiology (ZIHP), Zurich 8057, Switzerland.
6
Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
7
Institute for Integrative Physiology and Center for Systems Biology of O(2) Sensing, University of Chicago, Chicago, IL 60637, USA.
8
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA. Electronic address: lgodley@medicine.bsd.uchicago.edu.

Abstract

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.

PMID:
24835990
PMCID:
PMC4516227
DOI:
10.1016/j.celrep.2014.04.040
[Indexed for MEDLINE]
Free PMC Article

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