TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.
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.
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.
Christopher J
CJ
Mariani
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Aparna
A
Vasanthakumar
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Jozef
J
Madzo
Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
Ali
A
Yesilkanal
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Tushar
T
Bhagat
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yiting
Y
Yu
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Sanchari
S
Bhattacharyya
Institute of Physiology and Zurich Center for Human Physiology (ZIHP), Zurich 8057, Switzerland.
Roland H
RH
Wenger
Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
Susan L
SL
Cohn
Institute for Integrative Physiology and Center for Systems Biology of O(2) Sensing, University of Chicago, Chicago, IL 60637, USA.
Jayasri
J
Nanduri
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Amit
A
Verma
Institute for Integrative Physiology and Center for Systems Biology of O(2) Sensing, University of Chicago, Chicago, IL 60637, USA.
Nanduri R
NR
Prabhakar
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.
Lucy A
LA
Godley
D044503:5-Methylcytosine / Q000031:analogs & derivatives; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D006899:Mixed Function Oxygenases; D009447:Neuroblastoma / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020218:Response Elements; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human