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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.
Afiliação
  • Chakraborty AA; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Laukka T; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
  • Myllykoski M; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
  • Ringel AE; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Booker MA; Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Tolstorukov MY; Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Meng YJ; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Meier SR; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Jennings RB; Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
  • Creech AL; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Herbert ZT; The Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
  • McBrayer SK; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Olenchock BA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Jaffe JD; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Haigis MC; Molecular Biology Core Facility, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Beroukhim R; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Signoretti S; Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Koivunen P; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Kaelin WG; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Science ; 363(6432): 1217-1222, 2019 03 15.
Article em En | MEDLINE | ID: mdl-30872525
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxigênio / Proteínas Nucleares / Cromatina / Histona Desmetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxigênio / Proteínas Nucleares / Cromatina / Histona Desmetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article