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

被引：288

作者：

Chakraborty, Abhishek A. ^{[1
,2
]}

Laukka, Tuomas ^{[3
]}

Myllykoski, Matti ^{[3
]}

Ringel, Alison E. ^{[4
]}

Booker, Matthew A. ^{[5
]}

Tolstorukov, Michael Y. ^{[5
]}

Meng, Yuzhong Jeff ^{[1
,2
,6
,7
,8
,9
]}

Meier, Samuel R. ^{[6
]}

Jennings, Rebecca B. ^{[10
]}

Creech, Amanda L. ^{[6
]}

Herbert, Zachary T. ^{[2
,11
]}

McBrayer, Samuel K. ^{[1
,2
]}

Olenchock, Benjamin A. ^{[12
,13
]}

Jaffe, Jacob D. ^{[6
]}

Haigis, Marcia C. ^{[4
]}

Beroukhim, Rameen ^{[1
,2
,6
,8
]}

Signoretti, Sabina ^{[10
]}

Koivunen, Peppi ^{[3
]}

Kaelin, William G., Jr. ^{[1
,2
,14
]}

机构：

[1] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA

[3] Univ Oulu, Bioctr Oulu, Fac Biochem & Mol Med, Oulu Ctr Cell Matrix Res, FIN-90014 Oulu, Finland

[4] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dana Farber Canc Inst, Dept Informat, Boston, MA 02215 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[7] Harvard Med Sch, Biol & Biomed Sci, Boston, MA 02115 USA

[8] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[9] Harvard Med Sch, Harvard MIT Program Hlth Sci & Technol, Boston, MA 02115 USA

[10] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[11] Harvard Med Sch, Dana Farber Canc Inst, Mol Biol Core Facil, Boston, MA 02215 USA

[12] Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA

[13] Harvard Med Sch, Boston, MA 02115 USA

[14] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

SCIENCE | 2019年 / 363卷 / 6432期

基金：

芬兰科学院;

关键词：

RNA-SEQ; HYPOXIA; DIFFERENTIATION; INHIBITOR; IDH; UTX;

D O I：

10.1126/science.aaw1026

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1217 / +

页数：72

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