Format

Send to

Choose Destination
Science. 2019 Mar 15;363(6432):1217-1222. doi: 10.1126/science.aaw1026. Epub 2019 Mar 14.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
2
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
3
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
6
Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
8
The Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
10
Molecular Biology Core Facility, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
11
Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
12
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland. william_kaelin@dfci.harvard.edu peppi.karppinen@oulu.fi.
13
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. william_kaelin@dfci.harvard.edu peppi.karppinen@oulu.fi.
14
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

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.

Comment in

PMID:
30872525
DOI:
10.1126/science.aaw1026

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center