Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Free Radic Biol Med. 2013 Sep;64:20-30. doi: 10.1016/j.freeradbiomed.2013.05.022. Epub 2013 May 24.
Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short noncoding RNAs that regulate gene expression through posttranscriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in the expression of a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated in order to integrate into the complex hierarchical regulatory network induced by hypoxia.
缺氧，或低氧张力，是一种独特的环境压力，它诱导转录因子和信号蛋白的复杂调控网络发生全局变化，以协调细胞在代谢、增殖、DNA 修复和细胞凋亡方面的适应。现在有几条证据表明，微小 RNA（miRNAs）是通过转录后机制调节基因表达的短非编码 RNA，是对缺氧反应的关键因素。缺氧诱导特定一组 miRNAs（称为低氧 miRNAs）的表达发生明显变化，并且新兴证据表明，缺氧调节低氧 miRNAs 转录、成熟和功能的几个方面。在缺氧条件下，转录因子如缺氧诱导因子被上调，并直接激活一组低氧 miRNAs 的转录。相反，缺氧通过不太明确的机制选择性地抑制其他低氧 miRNAs。此外，缺氧还直接涉及到表观遗传修饰，如 DNA 去甲基化，从而控制特定 miRNA 的转录。最后，缺氧还调节控制 miRNA 成熟和活性的关键蛋白的活性。综上所述，这些发现确立了缺氧作为 miRNA 生物发生和功能的重要近端调节因子。未来的研究将需要解决转录和转录后事件在调节特定低氧 miRNAs 中的相对贡献，以及这些 miRNAs 如何协调以整合到由缺氧诱导的复杂层次调控网络中，这将是很重要的。
