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Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis

ABSTRACT: three replicates of HT29 cells per conditionwere grown under normoxic and hypoxic conditions. RNA and miRNA was extracted from each replicate and run on the GPL570 and GPL5106 arrays respectively. Low levels of oxygen in tissues, seen in situations such as chronic lung disease, necrotic tumors, and high altitude exposures, initiate a signaling pathway that results in active transcription of genes possessing a hypoxia response element (HRE). To identify changes induced by hypoxia and determine whether miRNA may have effects on gene expression, we conducted mRNA- and miRNA-array-based analysis on HT29 cells, and developed methods for the comparative analysis of these data sets. To date, no studies have examined the effects of an environmental perturbation on miRNA levels and their relationship to gene expression. Comparison of miRNAs with the expression of their predicted targets indicated a lower level of concordance than expected. We did, however, find preliminary evidence of combinatorial regulation of mRNA expression by miRNA. The methods described here for comparative analysis of miRNA and mRNA profiling will be useful for better understanding genome wide regulatory responsiveness, and to refine miRNA predictive algorithms under development for that purpose. Keywords: miRNA, hypoxia, HT29, cystic fibrosis

ORGANISM(S): Rattus norvegicus Mus musculus Homo sapiens

PROVIDER: GSE9234 | GEO | 2008/03/01

SECONDARY ACCESSION(S): PRJNA102837

REPOSITORIES: GEO

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Project description:In humans and other species, Longlong-term hypoxia (LTH) during pregnancy can lead to intrauterine growth restriction with reduced body/brain weight, dysregulation of cerebral blood flow (CBF), and other problems in humans and rodents. In contrast, sheep appear to undergo relatively successful acclimatization, not demonstrating any of the above-mentioned problems except at extremely high altitude. To identify the signal transduction genetic pathways and those critical molecules, which may be involved in acclimatization to high altitude LTH, we conducted microarray with advanced bioinformatic analysis on carotid arteries (CA) from the normoxic near-term ovine fetus at sea-level and those acclimatized to high altitude for 110+ days during gestation. In response to LTH acclimatization, in fetal CA we identified, mRNA from 38 genes upregulated (> 2 fFold; (P < 0.05) and 9 genes downregulated (> 2-f Fold; (P < 0.05). The major genes with upregulated mRNA were SLC1A3, Insulin-like growth factor (IGF) binding protein 3, IGF type 2 receptor, transforming growth factor (TGF) Beta-3, and genes involved in the AKT and BCL2 signal transduction networks. The majority of genes with upregulated mRNA have a common motif for Pbx/Knotted homeobox in the promoter region, and Sox family binding sites in the 3M-bM-^@M-^Y un -translated region (UTR). Genes with downregulated mRNA included those involved in the P53 pathway and 5-lipoxygenase activating proteins. The promoter region of all genes with downregulated mRNA, had a common 49 bp region, with a binding site for DOT6 and TOD6, components of the RPD3 histone deacetylase complex RPD3C(L). We also identified miRNA complementary to a number of the altered genes. Thus, the present study identified molecules in the ovine fetus, which may help it to play a role in the acclimatizatione successfully response to high-altitude associated LTH. In these series of experiments we examined changes in gene expression in sheep carotids. Pregnant sheep and non-pregnant adult sheep were exposed to 110 days of hypoxia at 3801 meters of altitude. Carotid arteries from fetuses from non-pregnant adult from sea-level controls and those from high-altitude were compared by Agilent ovine custom array

Project description:Background: The number of red blood cells (RBCs) increases significantly in response to high-altitude hypoxic environments, and the RBC microRNA (miRNA) expression pattern is similar to that in whole blood. Studies have shown that miRNA in plasma can act as a circulating hypoxia-associated marker, but the effect of a high-altitude hypoxic environment on RBC-derived miRNAs has not yet been reported. Methods: Blood samples were collected from 20 Han Chinese individuals residing at 500 m (Sichuan Han), 10 migrant Han Chinese citizens residing at 3658 m (Tibet Han) and 12 native Tibetans, and RBC indices measurements and miRNA sequencing analyses were performed for the three sample groups. The levels of some markedly altered miRNAs at high altitude were subsequently measured from 5 randomly selected samples of each group by real-time PCR. Bioinformatic analyses was performed to determine the potential target genes of selected hypoxia-associated miRNAs. Results: Marked changes of several RBC indices were observed among the Tibet Han population, the Tibetan population and the Sichuan Han population. A total of 516 miRNAs derived from RBCs were initially identified by miRNA sequencing in the three sample groups. Compared with the Sichuan Han population, 49 miRNAs were differentially expressed in the Tibet Han population (17 upregulated and 32 downregulated). 12 upregulated and 21 downregulated miRNAs were observed in the Tibetan population compared with the Sichuan Han population. A total of 40 RBC miRNAs were differentially expressed in the Tibetan population (15 upregulated and 25 downregulated) compared with the Tibet Han population. Two significantly altered miRNAs with the highest expression levels (miRNA-144-5p and miR-30b-5p) were selected for real-time PCR analysis, and the results were consistent with those of miRNA sequencing. Furthermore, bioinformatic analyses showed that some potential target genes of miR-144-5p and miR-30b-5p are involved in the erythroid- hypoxia-, and nitric oxide (NO)-related signaling pathways in response to hypoxia. Conclusion: Our findings provide clear evidence, for the first time, that a high-altitude hypoxic environment significantly affects human RBC miRNA profiles.

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Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis

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