Hypoxia: a master regulator of microRNA biogenesis and activity

Abstract

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.

Keywords: 3′ untranslated region; 3′UTR; Ago2; Argonaute 2; CCN5; CUL2; ChIP; DGCR8; DMNT; DNA methyltransferase; Di George syndrome critical region 8; E2F transcription factor 3; E2F3; Free radicals; HIF; HRE; HUVEC; Hypoxamir; Hypoxia; MicroRNA; NF-κB; ODD; PTM; ROS; TF; TNF receptor-associated factor 6; TRAF6; TWIST1; Twist-related protein 1; UPR; VHL; chromatin immunoprecipitation; cullin2; cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5; human umbilical vein endothelial cell; hypoxia-inducible factor; hypoxia-responsive element; mTOR; mammalian target of rapamycin; miRISC; miRNA; miRNA-induced silencing complex; microRNA; nuclear factor-κB; oxygen-dependent domain; posttranslational modification; pre-miRNA; precursor miRNA; pri-miRNA; primary microRNA; reactive oxygen species; transcription factor; unfolded protein response; von Hippel-Lindau tumor suppressor protein.