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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1217-1222 |
| Number of pages | 6 |
| Journal | Science |
| Volume | 363 |
| Issue number | 6432 |
| DOIs | |
| State | Published - Jan 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- General
Cite this
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, William G.
In: Science, Vol. 363, No. 6432, 01.01.2019, p. 1217-1222.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate
AU - Chakraborty, Abhishek A.
AU - Laukka, Tuomas
AU - Myllykoski, Matti
AU - Ringel, Alison E.
AU - Booker, Matthew A.
AU - Tolstorukov, Michael Y.
AU - Meng, Yuzhong Jeff
AU - Meier, Samuel R.
AU - Jennings, Rebecca B.
AU - Creech, Amanda L.
AU - Herbert, Zachary T.
AU - McBrayer, Samuel K.
AU - Olenchock, Benjamin A.
AU - Jaffe, Jacob D.
AU - Haigis, Marcia C.
AU - Beroukhim, Rameen
AU - Signoretti, Sabina
AU - Koivunen, Peppi
AU - Kaelin, William G.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062942396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062942396&partnerID=8YFLogxK
U2 - 10.1126/science.aaw1026
DO - 10.1126/science.aaw1026
M3 - Article
C2 - 30872525
AN - SCOPUS:85062942396
VL - 363
SP - 1217
EP - 1222
JO - Science
JF - Science
SN - 0036-8075
IS - 6432
ER -