The TIP60 Complex Is a Conserved Coactivator of HIF1A

Cell Rep. 2016 Jun 28;16(1):37-47. doi: 10.1016/j.celrep.2016.05.082. Epub 2016 Jun 16.


Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. Despite their established roles in normal physiology and numerous pathologies, the molecular mechanisms by which they control gene expression remain poorly understood. We report here a conserved role for the TIP60 complex as a HIF1 transcriptional cofactor in Drosophila and human cells. TIP60 (KAT5) is required for HIF1-dependent gene expression in fly cells and embryos and colorectal cancer cells. HIF1A interacts with and recruits TIP60 to chromatin. TIP60 is dispensable for HIF1A association with its target genes but is required for HIF1A-dependent chromatin modification and RNA polymerase II activation in hypoxia. In human cells, global analysis of HIF1A-dependent gene activity reveals that most HIF1A targets require either TIP60, the CDK8-Mediator complex, or both as coactivators for full expression in hypoxia. Thus, HIF1A employs functionally diverse cofactors to regulate different subsets of genes within its transcriptional program.

MeSH terms

  • Acetylation
  • Animals
  • Chromatin / metabolism
  • Conserved Sequence*
  • Cyclin-Dependent Kinase 8 / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • HCT116 Cells
  • HEK293 Cells
  • Histone Acetyltransferases / metabolism*
  • Histones / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lysine Acetyltransferase 5 / metabolism*
  • Protein Binding
  • Protein Subunits / metabolism
  • RNA Polymerase II / metabolism
  • Transcription, Genetic
  • Transcriptional Activation


  • Chromatin
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Histones
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Subunits
  • Sima protein, Drosophila
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • Tip60 protein, Drosophila
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • RNA Polymerase II