ZFIN ID: ZDB-PUB-171017-1
Tet1 facilitates hypoxia tolerance by stabilizing the HIF-α proteins independent of its methylcytosine dioxygenase activity
Wang, J., Zhang, D., Du, J., Zhou, C., Li, Z., Liu, X., Ouyang, G., Xiao, W.
Date: 2017
Source: Nucleic acids research   45(22): 12700-12714 (Journal)
Registered Authors: Ouyang, Gang, Wang, Jing, Xiao, Wuhan
Keywords: none
MeSH Terms:
  • 5-Methylcytosine/metabolism
  • Adaptation, Physiological/genetics
  • Animals
  • Apoptosis/genetics
  • Basic Helix-Loop-Helix Transcription Factors/genetics*
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Brain/metabolism
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Dioxygenases/genetics*
  • Dioxygenases/metabolism
  • Gene Expression Regulation
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  • Mice, Knockout
  • Proto-Oncogene Proteins/genetics*
  • Proto-Oncogene Proteins/metabolism
  • Signal Transduction/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 29036334 Full text @ Nucleic Acids Res.
Because of the requirement of oxygen (O2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor α (HIF-α) and enhances HIF-α transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2α and HIF-1α through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2α, resulting in a reduction of HIF-2α hydroxylation by PHD2. For HIF-1α, however, Tet1 has no effect on HIF-1α hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1α by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-α. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling.