@article{dac7bd34978249f5a2b53401561aa2fb,
title = "Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate",
abstract = "Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.",
author = "Chakraborty, {Abhishek A.} and Tuomas Laukka and Matti Myllykoski and Ringel, {Alison E.} and Booker, {Matthew A.} and Tolstorukov, {Michael Y.} and Meng, {Yuzhong Jeff} and Meier, {Samuel R.} and Jennings, {Rebecca B.} and Creech, {Amanda L.} and Herbert, {Zachary T.} and McBrayer, {Samuel K.} and Olenchock, {Benjamin A.} and Jaffe, {Jacob D.} and Haigis, {Marcia C.} and Rameen Beroukhim and Sabina Signoretti and Peppi Koivunen and Kaelin, {William G.}",
note = "Funding Information: We thank H. Zhao, D. Lambrechts, and P. Carmeliet for sharing their TCGA tumor annotations. We thank R. Looper for synthesizing and sharing the esterified 2-HG, M. K. Koski and R. Wierenga for help with structural modeling, and T. Aatsinki and E. Lehtimaki for technical assistance. We thank the Broad GDAC group for help with the GDAC-GSEA source code. We thank M. Oser for sharing mouse KDM5A sgRNAs and V. Koduri for assistance in acquiring microscopic images. Funding: W.G.K. was supported by grants from the NIH (R01CA068490, P50CA101942, and R35CA210068). A.A.C. was supported by grants from the Friends of Dana-Farber and the NIH (Cancer Biology Training grant: T32CA009361 and the DF/HCC Kidney SPORE CEP and DRP award: P50CA101942). P.K. was supported by Academy of Finland grants (266719 and 308009), the S. Juselius Foundation, the Jane and Aatos Erkko Foundation, and the Finnish Cancer Organizations. T.L. was supported by the Finnish Medical Foundation and, with P.K., the Emil Aaltonen Foundation. S.K.M. is supported by an American Cancer Society postdoctoral fellowship (PF-14-144-01-TBE) and by a Career Enhancement Project award from the Dana-Farber/Harvard Cancer Center Brain SPORE. W.G.K. is an HHMI Investigator. Publisher Copyright: {\textcopyright} 2019 American Association for the Advancement of Science. All rights reserved.",
year = "2019",
doi = "10.1126/science.aaw1026",
language = "English (US)",
volume = "363",
pages = "1217--1222",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6432",
}