Suzuki Norio, Gradin Katarina, Poellinger Lorenz, Yamamoto Masayuki
Division of Oxygen Biology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
Exp Cell Res. 2017 Jul 15;356(2):182-186. doi: 10.1016/j.yexcr.2017.03.013. Epub 2017 Mar 9.
Hypoxia causes dramatic changes in the expression profiles of genes that encode glycolytic enzymes, vascular endothelial growth factors, erythropoietin, and other factors in a tissue-specific manner through activating hypoxia-inducible transcription factors (HIFs) such as HIF1α and HIF2α. It has been elucidated that the activity of HIFs is fundamentally regulated by their protein stability in an oxygen-dependent manner. However, little is known about how stabilized HIFs regulate transcription of their target genes in hypoxic cells. Additionally, the roles of HIF3α, the third member of the HIFs, are still enigma due to its various splicing variants and the complicated phenotypes of Hif3a-gene modified mouse lines. Here, we summarize how molecular systems fine-tune hypoxia-inducible transcription with the cooperation of HIFs and their negative regulators, including IPAS, one of the HIF3α splicing variants. Since epigenetic mechanisms contribute to stress-inducible and cell-type specific gene regulation, the HIF-dependent reorganization of nucleosome structures in hypoxia-inducible gene promoters is also discussed.
缺氧通过激活缺氧诱导转录因子（HIFs），如HIF1α和HIF2α，以组织特异性方式导致编码糖酵解酶、血管内皮生长因子、促红细胞生成素和其他因子的基因表达谱发生显著变化。据阐明，HIFs的活性从根本上以氧依赖方式由其蛋白质稳定性调节。然而，关于稳定化的HIFs如何调节缺氧细胞中其靶基因的转录知之甚少。此外，HIFs的第三个成员HIF3α的作用仍不明朗，这是由于其各种剪接变体以及Hif3a基因修饰小鼠品系的复杂表型。在此，我们总结分子系统如何通过HIFs及其负调节因子（包括HIF3α剪接变体之一IPAS）的协同作用来微调缺氧诱导转录。由于表观遗传机制有助于应激诱导和细胞类型特异性基因调控，因此还讨论了缺氧诱导基因启动子中依赖HIF的核小体结构重组。
