United States Department of Transportation
i
Human Bronchial Epithelial Cells Display Alterations in Chromatin Accessibility and Gene Expression According to Oxygen Availability
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2021-03-01
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Abstract:Aircraft passengers and crew experience mild hypoxia during flight equivalent to an 8,000-ft elevation. Hypoxia is known to induce physiological and transcriptional changes that function together to permit normal cellular and tissue function at reduced oxygen (O2) levels. Short-term physiological responses include increased respiration and mild tachycardia; short-term transcriptional responses promote glycolysis and initiate angiogenesis, hematopoiesis, and other mitigating adaptations. Hypoxia also induces changes in nuclear chromatin structure, altering histone methylation and chromatin accessibility profiles to promote or inhibit the transcription of specific genes. We assayed chromatin accessibility and gene expression in human bronchial epithelial cells (HBECs) treated at 21%, 15% (the equivalent of aircraft cabin pressurization), and 2% O2 (typical of tissue hypoxia). Large-scale changes in chromatin accessibility and gene expression were observed at 15% O2, including upregulation of histone genes and a reduction in intergenic and intronic chromatin accessibility. The 2% O2 treatment exhibited fewer changes in relation to the 21% O2 treatment and were mainly limited to the hypoxic response. ANGPTL4, an angiogenic regulator, increased at 2% O2 but decreased at 15% O2. Further, downregulation of the master regulator of the hypoxic response, HIF1α, was predicted at 15% O2 based on the expression status of the genes it regulates. In summary, HBECs exposed to 15% O2 for 16 hours exhibit a large-scale transcriptional and nucleosomal response that appears to exclude most hypoxia regulators and, instead, triggers a response possibly promoting altitude acclimatization.
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