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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

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

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Author: Chakraborty, Abhishek A.1; Laukka, Tuomas2; Myllykoski, Matti2;
Organizations: 1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
2Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland
3Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
4Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
5Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
6Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
7Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
8The Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
9Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
10Molecular Biology Core Facility, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
11Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
12Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 6.5 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201903259863
Language: English
Published: American Association for the Advancement of Science (AAAS), 2019
Publish Date: 2019-03-25
Description:

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.

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Series: Science
ISSN: 0036-8075
ISSN-E: 1095-9203
ISSN-L: 0036-8075
Volume: 363
Issue: 6432
Pages: 1217 - 1222
DOI: 10.1126/science.aaw1026
OADOI: https://oadoi.org/10.1126/science.aaw1026
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Article
Funding: W.G.K. was supported by grants from the NIH (R01CA068490, P50CA101942, and R35CA210068). A.A.C. was supported by grants from the Friends of Dana-Farber and the NIH (Cancer Biology Training grant: T32CA009361 and the DF/HCC Kidney SPORE CEP and DRP award: P50CA101942). P.K. was supported by Academy of Finland grants (266719 and 308009), the S. Juselius Foundation, the Jane and Aatos Erkko Foundation, and the Finnish Cancer Organizations. T.L. was supported by the Finnish Medical Foundation and, with P.K., the Emil Aaltonen Foundation. S.K.M. is supported by an American Cancer Society postdoctoral fellowship (PF-14-144-01-TBE) and by a Career Enhancement Project award from the Dana-Farber/Harvard Cancer Center Brain SPORE. W.G.K. is an HHMI Investigator.
Academy of Finland Grant Number: 266719
308009
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
Copyright information: © 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.