Histone modifiers are oxygen sensors.

Abstract

Hypoxia signals directly to chromatin via histone demethylases to alter gene expression Approximately 2.6 billion years ago, during the Proterozoic period, the evolution of photosynthesis in cyanobacteria led to the introduction of the by-product of this reaction, oxygen, into Earth's atmosphere ( 1 ). This great oxidative event heralded the rise of multicellular organisms, which are almost totally dependent on oxygen as an efficient fuel for metabolism and as a cofactor in many critical physiological enzymatic reactions. Central to this adaptation, and to allow cellular physiology across a wide range of oxygen concentrations (tensions), metazoans have evolved the highly conserved hypoxia-inducible factor (HIF) pathway ( 2 ). This is important for both physiological and pathological processes that occur in a hypoxic microenvironment, including embryogenesis, stem cell homeostasis, cancer, and cardiovascular disease. It has long been observed that hypoxia induces histone lysine hypermethylation, a form of epigenetic chromatin modification. However, whether this represents a direct sensing of oxygen tension or an indirect effect, perhaps through the HIF pathway, has not been established ( 3 ). On pages 1222 and 1217 of this issue, Batie et al. ( 4 ) and Chakraborty et al. ( 5 ), respectively, resolve this question, demonstrating in different cellular systems that the activity of the lysine-specific demethylases (KDMs) KDM5A and KDM6A is oxygen sensitive, and thereby identifying them as oxygen sensors.