组蛋白去甲基化酶 KDM6A 直接感知氧气以控制染色质和细胞命运。
Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
出版信息
Science. 2019 Mar 15;363(6432):1217-1222. doi: 10.1126/science.aaw1026. Epub 2019 Mar 14.
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.
氧感应是后生动物生物学的核心，对人类疾病有影响。哺乳动物细胞表达多种称为 2- 酮戊二酸（2-OG）依赖性双氧酶（2-OGDD）的氧依赖性酶，但它们的氧亲和力不同，因此氧感应能力也不同。2-OGDD 组蛋白去甲基酶控制组蛋白甲基化。缺氧会增加组蛋白甲基化，但这是否反映了对组蛋白去甲基酶的直接影响，还是由于缺氧诱导 HIF（缺氧诱导因子）转录因子或 2-OG 拮抗剂 2- 羟基戊二酸（2-HG）间接引起的，目前尚不清楚。在这里，我们报告说，缺氧以 HIF 和 2-HG 独立的方式促进组蛋白甲基化。我们发现，H3K27 组蛋白去甲基酶 KDM6A/UTX，但不是其同源物 KDM6B，对氧敏感。KDM6A 缺失，就像缺氧一样，阻止了 H3K27 去甲基化并阻止了细胞分化。在缺氧细胞中恢复 H3K27 甲基化平衡逆转了这些效应。因此，氧直接影响染色质调节剂来控制细胞命运。
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