Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate
Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate
复制标题
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
DOI：
10.1126/science.aaw1026
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发表时间：
2019-03-15
期刊：
影响因子：
56.9
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Chakraborty, Abhishek A.;Laukka, Tuomas;Kaelin, William G., Jr.
氧感应是后生动物生物学的核心，对人类疾病也有影响。哺乳动物细胞表达多种氧依赖性酶，称为2-氧戊二酸（OG）依赖性双加氧酶（2- ogdd），但它们的氧亲和力不同，因此它们感知氧的能力也不同。2-OGDD组蛋白去甲基化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化酶的直接影响，还是缺氧诱导HIF（缺氧诱导因子）转录因子或2-OG拮抗剂2-羟戊二酸（2-HG）引起的间接影响尚不清楚。在这里，我们报告了缺氧以hif和2- hg不依赖的方式促进组蛋白甲基化。我们发现H3K27组蛋白去甲基化酶KDM6A/UTX对氧敏感，而与之平行的KDM6B不敏感。KDM6A缺失，像缺氧一样，阻止H3K27去甲基化并阻断细胞分化。在缺氧细胞中恢复H3K27甲基化稳态逆转了这些作用。因此，氧直接影响染色质调节因子来控制细胞命运。
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.