DOI: 10.1101/510479Jan 3, 2019Paper

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

BioRxiv : the Preprint Server for Biology
Abhishek A ChakrabortyW G Kaelin

Abstract

Mammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF- and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.

Related Concepts

Allergens
Cell Differentiation Process
Chromatin
Histones
Oxygen
Transcription Factor
alpha-hydroxyglutarate
Hypoxia
Chromatin protein
Dioxygenases

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