Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate

Chakraborty, Abhishek A.; Laukka, Tuomas; Myllykoski, Matti; Ringel, Alison E.; Booker, Matthew A.; Tolstorukov, Michael Y.; Meng, Yuzhong Jeff; Meier, Samuel R.; Jennings, Rebecca B.; Creech, Amanda L.; Herbert, Zachary T.; McBrayer, Samuel K.; Olenchock, Benjamin A.; Jaffe, Jacob D.; Haigis, Marcia C.; Beroukhim, Rameen; Signoretti, Sabina; Koivunen, Peppi; Kaelin Jr., William G. (2019-03-15)
 
Avaa tiedosto
Lataukset: 

URL:
https://doi.org/10.1126/science.aaw1026

Chakraborty, Abhishek A.
Laukka, Tuomas
Myllykoski, Matti
Ringel, Alison E.
Booker, Matthew A.
Tolstorukov, Michael Y.
Meng, Yuzhong Jeff
Meier, Samuel R.
Jennings, Rebecca B.
Creech, Amanda L.
Herbert, Zachary T.
McBrayer, Samuel K.
Olenchock, Benjamin A.
Jaffe, Jacob D.
Haigis, Marcia C.
Beroukhim, Rameen
Signoretti, Sabina
Koivunen, Peppi
Kaelin Jr., William G.
American Association for the Advancement of Science (AAAS)
15.03.2019

Chakraborty, A., Laukka, T., Myllykoski, M., Ringel, A., Booker, M., Tolstorukov, M., Meng, Y., Meier, S., Jennings, R., Creech, A., Herbert, Z., McBrayer, S., Olenchock, B., Jaffe, J., Haigis, M., Beroukhim, R., Signoretti, S., Koivunen, P., Kaelin, W. (2019) Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science, 363 (6432), 1217-1222. doi:10.1126/science.aaw1026

https://rightsstatements.org/vocab/InC/1.0/
© 2018 The Authors. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on Vol. 363, Issue 6432, pp. 1217-1222, 15 Mar 2019, https://doi.org/10.1126/science.aaw1026.
https://rightsstatements.org/vocab/InC/1.0/
doi:https://doi.org/10.1126/science.aaw1026
Näytä kaikki kuvailutiedot
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi-fe201903259863
Tiivistelmä

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.

Kokoelmat