TY - JOUR
T1 - TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma
AU - Mariani, Christopher J.
AU - Vasanthakumar, Aparna
AU - Madzo, Jozef
AU - Yesilkanal, Ali
AU - Bhagat, Tushar
AU - Yu, Yiting
AU - Bhattacharyya, Sanchari
AU - Wenger, Roland H.
AU - Cohn, Susan L.
AU - Nanduri, Jayasri
AU - Verma, Amit
AU - Prabhakar, Nanduri R.
AU - Godley, Lucy A.
N1 - Funding Information:
We would like to thank Marsha Rosner for the TET1 shRNA plasmid and Chuan He for UDP-6-N3-glucose. We thank Jeremy Marks and Angela Stoddart for comments on the manuscript and insightful discussions. This work was supported in part by NIH grants T32-HD007009-38 (to C.J.M.) and P01-HL090554-06 (to N.R.P.).
PY - 2014/6/12
Y1 - 2014/6/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2014.04.040
DO - 10.1016/j.celrep.2014.04.040
M3 - Article
C2 - 24835990
AN - SCOPUS:84902345994
SN - 2211-1247
VL - 7
SP - 1343
EP - 1352
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -