RT Journal Article
SR Electronic
T1 The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 510479
DO 10.1101/510479
A1 Abhishek A. Chakraborty
A1 Tuomas Laukka
A1 Matti Myllykoski
A1 Alison E. Ringel
A1 Matthew A. Booker
A1 Michael Y. Tolstorukov
A1 Yuzhong Jeff Meng
A1 Sam Meier
A1 Rebecca B. Jennings
A1 Amanda L. Creech
A1 Zachary T. Herbert
A1 Jessica Spinelli
A1 Samuel K. McBrayer
A1 Benjamin A. Olenchock
A1 Jacob D. Jaffe
A1 Marcia C. Haigis
A1 Rameen Beroukhim
A1 Sabina Signoretti
A1 Peppi Koivunen
A1 William G. Kaelin, Jr.
YR 2019
UL http://biorxiv.org/content/early/2019/01/03/510479.abstract
AB 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.One Sentence Summary KDM6A demethylase activity is diminished under hypoxic conditions and causes changes in gene expression programs that govern cell fate.