TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma

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

Research output: Contribution to journalArticle

78 Scopus citations

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 inpart 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.

Original languageEnglish (US)
Pages (from-to)1343-1352
Number of pages10
JournalCell Reports
Volume7
Issue number5
DOIs
StatePublished - Jun 12 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mariani, C. J., Vasanthakumar, A., Madzo, J., Yesilkanal, A., Bhagat, T., Yu, Y., Bhattacharyya, S., Wenger, R. H., Cohn, S. L., Nanduri, J., Verma, A., Prabhakar, N. R., & Godley, L. A. (2014). TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Reports, 7(5), 1343-1352. https://doi.org/10.1016/j.celrep.2014.04.040