Hypoxia induces rapid changes to histone methylation and reprograms chromatin

Science. 2019 Mar 15;363(6432):1222-1226. doi: 10.1126/science.aau5870. Epub 2019 Mar 14.


Oxygen is essential for the life of most multicellular organisms. Cells possess enzymes called molecular dioxygenases that depend on oxygen for activity. A subclass of molecular dioxygenases is the histone demethylase enzymes, which are characterized by the presence of a Jumanji-C (JmjC) domain. Hypoxia can alter chromatin, but whether this is a direct effect on JmjC-histone demethylases or due to other mechanisms is unknown. Here, we report that hypoxia induces a rapid and hypoxia-inducible factor-independent induction of histone methylation in a range of human cultured cells. Genomic locations of histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3 after a brief exposure of cultured cells to hypoxia predict the cell's transcriptional response several hours later. We show that inactivation of one of the JmjC-containing enzymes, lysine demethylase 5A (KDM5A), mimics hypoxia-induced cellular responses. These results demonstrate that oxygen sensing by chromatin occurs via JmjC-histone demethylase inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Cell Hypoxia
  • Chromatin / metabolism*
  • Fibroblasts
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Oxygen / metabolism*
  • Protein Domains
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors
  • Retinoblastoma-Binding Protein 2 / chemistry
  • Retinoblastoma-Binding Protein 2 / genetics
  • Retinoblastoma-Binding Protein 2 / metabolism*


  • Amino Acids, Dicarboxylic
  • Chromatin
  • Histones
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2
  • Lysine
  • Oxygen
  • oxalylglycine