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

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

doi:10.1126/science.aaw1026

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

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

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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	https://doi.org/10.1126/science.aaw1026
State	Published - 2019
Externally published	Yes

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

Chakraborty, AA, Laukka, T, Myllykoski, M, Ringel, AE, Booker, MA, Tolstorukov, MY, Meng, YJ, Meier, SR, Jennings, RB, Creech, AL, Herbert, ZT, McBrayer, SK, Olenchock, BA, Jaffe, JD, Haigis, MC, Beroukhim, R, Signoretti, S, Koivunen, P & Kaelin, WG 2019, 'Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate', Science, vol. 363, no. 6432, pp. 1217-1222. https://doi.org/10.1126/science.aaw1026

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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.}",

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AU - Booker, Matthew A.

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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

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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.

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

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