Study On Sequence Variations And Hypoxia-Induced Expression In Isf1/Isfbp1Genes Of Oinghai-Tibet Plateau Microtus Oeconomus

Microtus oeconomus (M oeconomus) was studied as a hypoxia-adapted mammal. We compared its hypoxia-induced insulin-like growth factor1(Igf1) and insulin-like growth factor binding protein1(Igfbp1) gene expression and related sequence variants with the lowland mouse (Mus musculus), and investigated mechanisms of hypoxia-induced Igf1/Igfbp1regulation at transcriptional and post-transcriptional level, aiming to explore the molecular mechanisms of hypoxia adaptation.We cloned and analyzed the Igf1and Igfbp1genes of M. oeconomus, and found that the B, C, A, D domain in IGF1and the N, Central linker, C domain in IGFBP1were highly conserved with their counterparts in mouse, rat and human. The critical sites for IGF-IGFBP and IGF-IGFR binding also showed highly conservation. After acute hypoxia (8.0%O2,6h), hepatic Igf1gene expression and total IGF1content in plasma were unchanged in both M. oeconomus and mouse. Hypoxia significantly upregulated hepatic Igfbp1gene expression and IGFBP1content in the plasma of the lowland mouse, but not in M. oeconomus. In vitro, hypoxia upregulated M. oeconomus and mouse Igfl promoters’ activity, and HIF1was involved in the hypoxia-induced M. oeconomus promoter1transactivation. The regulatory regions of the M. oeconomus and mouse Igfbpl gene were not transcriptionally activated by hypoxia, while at post-transcriptional level, a functional U-rich element was found in the3’untranslated region (3’-UTR) of mouse Igfbpl mRNA which was involved in hypoxia-induced Igfbpl mRNA stabilization and hepatic Igfbpl upregulation. This U-rich element was eliminated in the M. oeconomus Igfbpl by gene variations, which resulted in blunted Igfbpl upregulation under hypoxia.This study provides partial sequences of the Igfl and Igfbpl genes in the Qinghai-Tibet plateau native mammal M. oeconomus, and investigates transcriptional regulation of Igfl/Igfbpl by hypoxia. At the post-transcriptional level, sequence variations in the M. oeconomus Igfbpl gene eliminate a functional U-rich element in the3’-UTR which results in the blunted Igfbpl mRNA stabilization and hepatic Igfbpl upregulation by hypoxia, and this may be a hypoxia adaptation strategy of native highland M. oeconomus.