ZFIN ID: ZDB-PUB-180822-1
Deletion of the fih gene encoding an inhibitor of hypoxia-inducible factors increases hypoxia tolerance in zebrafish.
Xiao, W., Cai, X., Zhang, D., Wang, J., Liu, X., Ouyang, G.
Date: 2018
Source: The Journal of biological chemistry   293(40): 15370-15380 (Journal)
Registered Authors: Ouyang, Gang, Wang, Jing, Xiao, Wuhan
Keywords: development, hydroxylase, hypoxia, tolerance, zebrafish
MeSH Terms:
  • Adaptation, Physiological/genetics*
  • Animals
  • Apoptosis/genetics
  • Brain/metabolism
  • Brain/physiopathology
  • CREB-Binding Protein/genetics
  • CREB-Binding Protein/metabolism
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Embryo, Nonmammalian
  • Epithelial Cells/metabolism
  • Epithelial Cells/pathology
  • Gene Deletion
  • Gene Editing/methods
  • Gene Expression Regulation, Developmental
  • Hypoxia/genetics*
  • Hypoxia/metabolism
  • Hypoxia/physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  • Mixed Function Oxygenases/deficiency
  • Mixed Function Oxygenases/genetics*
  • Mixed Function Oxygenases/metabolism
  • Oxygen Consumption/genetics
  • Protein Subunits/genetics
  • Protein Subunits/metabolism
  • Repressor Proteins/genetics*
  • Repressor Proteins/metabolism
  • Signal Transduction
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • p300-CBP Transcription Factors/genetics
  • p300-CBP Transcription Factors/metabolism
PubMed: 30126845 Full text @ J. Biol. Chem.
Many aerobic organisms have developed molecular mechanism to tolerate hypoxia, but the specifics of these mechanisms remain poorly understood. It is important to develop genetic methods that confer increased hypoxia tolerance to intensively farmed aquatic species, as these are maintained in environments with limited available oxygen. As an asparaginyl hydroxylase of hypoxia-inducible factors (HIFs), factor inhibiting HIF (FIH) inhibits transcriptional activation of hypoxia-inducible genes by blocking the association of HIFs with the transcriptional coactivators CREB-binding protein (CBP) and p300. Therefore, here we sought to test whether fih is involved in regulating hypoxia tolerance in the commonly used zebrafish model. Overexpressing the zebrafish fih gene in epithelioma papulosum cyprini (EPC) cells and embryos, we found that fih inhibits the transcriptional activation of zebrafish HIF-α proteins. Using CRISPR/Cas9 to obtain fih-null zebrafish mutants, we noted that the fih deletion makes zebrafish more tolerant of hypoxic conditions than their WT siblings, but does not result in oxygen consumption rates that significantly differ from those of WT fish. Of note, we identified fewer apoptotic cells in adult fih-null zebrafish brains and in fih-null embryos, possibly explaining why the fih-null mutant had greater hypoxia tolerance than the WT. Moreover, the fih deletion up-regulated several hypoxia-inducible genes in fih-null zebrafish exposed to hypoxia. The findings of our study suggest that fih plays a role in hypoxia tolerance by affecting the rate of cellular apoptosis in zebrafish.