TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.

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.

• Authors: Christopher J Mariani, Aparna Vasanthakumar, Jozef Madzo, Ali Yesilkanal, Tushar Bhagat, Yiting Yu, Sanchari Bhattacharyya, Roland H Wenger, Susan L Cohn, Jayasri Nanduri, Amit Verma, Nanduri R Prabhakar, Lucy A Godley
• Journal: Cell reports (Cell Rep) Vol. 7 Issue 5 Pg. 1343-1352 (Jun 12 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 24835990 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 5-Methylcytosine (analogs & derivatives)
• Cell Hypoxia
• Cell Line, Tumor
• Cytosine (analogs & derivatives, 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