miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells.
miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells.
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DOI：
10.1038/srep22775
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发表时间：
2016-03-08
影响因子：
4.6
通讯作者：
Collawn JF
中科院分区：
文献类型：
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作者：
Janaszak-Jasiecka A;Bartoszewska S;Kochan K;Piotrowski A;Kalinowski L;Kamysz W;Ochocka RJ;Bartoszewski R;Collawn JF
缺氧诱导因子（HIF）是一种异源二聚体转录因子，可使细胞在缺氧条件下适应并存活。HIF 1A和HIF 2A mRNA的调控已得到很好的表征，而HIF 3A mRNA的调控和功能尚不清楚。利用RNA-Seq分析原代人脐静脉内皮细胞，我们发现HIF 3A的两种亚型表达，HIF 3A 2和HIF 3A 3。比较HIF 3A和HIF 1A mRNA在缺氧48小时内的表达谱，发现HIF 1A的信息在4小时达到峰值，而HIF 3A的表达增加，而HIF 1A的表达减少。考虑到HIF 1A mRNA受miR-429调控，我们测试了miR-429对两种HIF 3A亚型的影响，发现它们也受miR-429调控。对HIF-3靶点DNA损伤诱导转录物4（一种关键存活基因）的分析表明，DDIT 4 mRNA受HIF-3诱导，并通过miR-429对HIF 3A信息的作用受到miR-429的负调控。这为缺氧诱导的miR-429如何通过快速降低HIF 1A水平，同时减缓HIF 3A表达的进展，直到miR-429水平降至含氧量正常水平以下，来调节HIF-1适应性反应与HIF-3存活反应之间的转换提供了一个令人信服的模型。由于HIF-1驱动HIF 3A和miR-429的表达，这建立了一个调控网络，其中miR-429发挥关键作用。
Hypoxia-inducible factors (HIF) are heterodimeric transcription factors that allow cells to adapt and survive during hypoxia. Regulation of HIF1A and HIF2A mRNA is well characterized, whereas HIF3A mRNA regulation and function are less clear. Using RNA-Seq analysis of primary human umbilical vein endothelial cells, we found two isoforms of HIF3A were expressed, HIF3A2 and HIF3A3. Comparing HIF3A expression profiles to HIF1A mRNA during 48 hours of hypoxia revealed that HIF1A message peaked at 4 hours, whereas HIF3A expression increased while HIF1A was decreasing. Given that HIF1A mRNA is regulated by miR-429, we tested miR-429 effects on both HIF3A isoforms and found that they too were regulated by miR-429. Analysis of a HIF-3 target, DNA-damage-inducible transcript 4, a key survival gene, indicated that DDIT4 mRNA is induced by HIF-3 and negatively regulated by miR-429 through miR-429’s actions on HIF3A message. This provides a compelling model for how hypoxia-induced miR-429 regulates the switch between HIF-1 adaptive responses to HIF-3 survival responses by rapidly decreasing HIF1A levels while simultaneously slowing the progression of HIF3A expression until the miR-429 levels drop below normoxic levels. Since HIF-1 drives HIF3A and miR-429 expression, this establishes a regulatory network in which miR-429 plays a pivotal role.