缺氧条件下，HIF1A 通过招募 CDK8 介导的中介体来刺激 RNAPII 延伸。
HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia.
机构信息
Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, CO 80309, USA.
出版信息
Cell. 2013 Jun 6;153(6):1327-39. doi: 10.1016/j.cell.2013.04.048.
The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.
转录因子 HIF1A 是细胞对缺氧反应的关键介质。尽管 HIF1A 在体内平衡和各种病理中具有重要作用，但人们对其如何调节 RNA 聚合酶 II（RNAPII）知之甚少。我们在这里报告，HIF1A 利用 Mediator 复合物的特定变体来刺激 RNAPII 延伸。与 paralog CDK19 不同，Mediator 相关激酶 CDK8 是诱导许多 HIF1A 靶基因所必需的。HIF1A 诱导 CDK8-Mediator 和包含 AFF4 和 CDK9 的超级延伸复合物（SEC）与 RNAPII 暂停结合。CDK8 对于 HIF1A 染色质结合和组蛋白乙酰化不是必需的，但对于 SEC 和 RNAPII 延伸的结合是必需的。对活性 RNAPII 的全面分析表明，缺氧诱导基因在诱导之前被暂停和激活。我们的研究结果为缺氧条件下细胞对 HIF1A 和 CDK8（两种潜在的致癌基因）的反应提供了一个机制联系。
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