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Effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes [methylation]

ABSTRACT: The predominant outcome of cardiovascular disease (CVD) is myocardial infarction (MI), where cardiomyocytes are deprived of oxygen. To study inter-individual differences in cardiomyocytes’ response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We characterized gene expression levels, chromatin accessibility, and methylation profiles in these cardiomyocytes in four culturing conditions that correspond to normoxia (10% O2), hypoxia (1% O2) and short or long-term re-oxygenation (back to 10% O2). In our population sample, 2,113 genes change their expression following hypoxia and short- or long-term re-oxygenation. Using available genotypes from all individuals, we identified 1,573 genes with a cis eQTL in at least one of the four culturing conditions. Taking into account the incomplete power to identify eQTLs in any given condition, we also identified 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of dynamic eQTLs, which are detected only following hypoxia, have not been previously annotated as eQTLs even in much larger collections of heart tissues. We did not detect differences in DNA methylation, or chromatin accessibility as the cells transitioned between normoxia and hypoxia, but we observed a change in chromatin accessibility in 831 genomic regions upon re-oxygenation. Differentially accessible regions are enriched for features of active regulatory regions, SINE elements, and E2F4 transcription factor binding sites . Finally, we found that genes associated with dynamic eQTLs are also associated with complex traits and disease. Our data thus demonstrate how unique genetic effects on gene expression, which are likely relevant for disease, can be uncovered under conditions of stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144425 | GEO | 2021/01/28

REPOSITORIES: GEO

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Project description:Oxygen fluctuation during tissue remodeling imposes a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastomas are believed to possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. To identify adaptive response mechanism, we compared the effects of acute and chronic hypoxia versus oxygenation on stem-like glioblastoma (GS) cells. GS cell lines were established and propagated either under normoxia (21% O2) or hypoxia (1% O2) and subsequently exposed to acute normoxia or hypoxia, respectively. Gene expression profiling revealed that acute hypoxia predominantly induced metabolic pathways and cell cycle arrest, whereas chronic hypoxia activated neurodevelopmental processes. In particular, we found increased expression of glycolytic enzymes, especially of the preparatory phase of glycolysis, under acute hypoxia, whereas pentose phosphate pathway (PPP) enzymes were downregulated. The opposite was found for acute oxygenation of hypoxic GS cells. Findings were confirmed by qPCR and immunoblot analyses. Despite downregulation by hypoxia, expression of PPP enzymes is increased in GBMs compared to normal brain, whereas expression of hypoxia-inducible enzymes of the parallel preparatory phase of glycolysis is decreased. Immunohistochemistry revealed strong staining for PPP enzymes in the bulk of GBM tissue, especially in highly proliferative areas, but not in pseudopalisading (hypoxic) cells. Glycolytic enzymes displayed an inverse pattern. Mass spectrometric analysis using [1,2-13C2]-D-glucose showed reduced glucose flux through the PPP under hypoxia in favor of flux through glycolysis. Acute and chronic hypoxia increased cell migration but reduced proliferation, whereas normoxia had opposite effects. Our findings extend Warburg’s observations by showing that in most tumor cells the PPP, which supplies metabolites for biomass production, is favored over the parallel preparatory phase of glycolysis, but is suppressed under acute severe hypoxia, causing a switch to direct glycolysis to protect against hypoxic stress.

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Effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes [methylation]

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