ABSTRACT
Our previous study revealed the particular expression patterns of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 1 (IGFBP1) in the Qinghai-Tibet plateau root vole (Microtus oeconomus) under hypoxic challenge. Here we report the molecular mechanisms of Igf gene regulation associated with adaptation to hypoxia. M. oeconomus IGF1 and IGFBP1 were shown to be highly conserved. Hypoxia (8.0% O2, 6h) did not change the liver-derived Igf1 expression in either M. oeconomus or mouse. Hypoxia significantly upregulated hepatic Igfbp1 gene expression and IGFBP1 levels in the liver and plasma of the mouse, but not in M. oeconomus. A functional U-rich element in the 3' untranslated region was found in mouse Igfbp1 mRNA, which was associated with Igfbp1 mRNA stabilization and upregulation under hypoxia, and this U-rich element was eliminated in the M. oeconomus Igfbp1, resulting in blunted Igfbp1 mRNA upregulation, which might be understood as a sequence variation modified during molecular evolution under hypoxia.
Subject(s)
Arvicolinae/genetics , Hypoxia/genetics , Insulin-Like Growth Factor Binding Protein 1/genetics , Insulin-Like Growth Factor I/genetics , Liver/metabolism , RNA, Messenger/genetics , Adaptation, Biological , Amino Acid Sequence , Animals , Arvicolinae/metabolism , Biological Evolution , Cell Line , Gene Expression Regulation , Hypoxia/metabolism , Insulin-Like Growth Factor Binding Protein 1/classification , Insulin-Like Growth Factor Binding Protein 1/metabolism , Insulin-Like Growth Factor I/classification , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Inbred ICR , Molecular Sequence Data , Phylogeny , RNA Stability , RNA, Messenger/metabolism , Sequence Alignment , TibetABSTRACT
Stress during gestation increases vulnerability to disease and changes behavior in offspring. We previously reported that hypoxia and restraint during pregnancy sensitized the hypothalamic-pituitary-adrenal (HPA) axis and induced anxiety-like behavior in the adult offspring. Here, we report that gestational intermittent hypoxia (GIH) elicited a sex-dependent anxiety-like behavior in male P90 offspring and activation of corticotropin-releasing hormone (CRH) and CRH type-1 receptor (CRHR1) mRNA in the hypothalamic paraventricular nucleus (PVN) and in male E19 hypothalamus. These linked to demethylation at several specific sites of CpG island of Crhr1 promoter in P90 PVN and E19 embryo hypothalamus in GIH groups. Crhr1 DNA demethylation is more crucial in CpG island 1 than island 2 for activation of CRHR1 mRNA. DNMT3b is required for the Crhr1 DNA methylation than DNMT1 and DNMT3a in increased CRHR1 mRNA. We first address a novel hypothesis that GIH-induced male-sex-dependent demethylation at CpG sites of Crhr1 DNA in promoter triggers elevation of CRHR1 mRNA in PVN and anxiety-like behavior in adult offspring.
