Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity.
Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity.
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HIF1α和HIF2α的N端和c端对其靶基因选择性的差异贡献
DOI：
10.3390/ijms21249401
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发表时间：
2020-12-10
影响因子：
5.6
通讯作者：
Aragonés J
中科院分区：
文献类型：
--
作者：
Bouthelier A;Meléndez-Rodríguez F;Urrutia AA;Aragonés J
细胞对缺氧的反应是由缺氧诱导的转录因子HIF1α和HIF2α控制的。一些基因优先被HIF1α或HIF2α诱导，正如在一些细胞模型和特定基因组中所探索的那样。在这里，我们使用体外WT8肾癌细胞和体内条件vhl缺陷小鼠模型，将该分析扩展到其他hif依赖性基因。此外，我们生成了嵌合的HIF1/2转录因子，以研究HIF1α和HIF2α DNA结合/异源二聚化和转激活结构域对HIF靶特异性的贡献。我们发现，在WT8细胞中诱导HIF2α依赖基因，如CAIX （CAR9）和BNIP3，需要HIF的两个半部分，而HIF2α反激活结构域与诱导HIF2靶基因（如氨基酸载体SLC7A5）更相关。WT8细胞中某些基因的HIF选择性在vhl缺陷的肺和肝组织中是保守的，而其他基因如Glut1 （Slc2a1）在这些组织中表现明显。因此，当比较HIF1α和HIF2α亚型时，DNA结合/异源二聚化和转激活结构域对HIF靶基因选择性的相对贡献可能不同，并且对于所分析的某些基因，HIF靶基因特异性在人和小鼠细胞中是保守的。
Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.
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影响因子：
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作者：
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通讯作者：
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