Changes in DNA Methylation after 24 Hours of High‐Altitude Exposure

Abstract

Acclimatization to high altitude involves a series of physiological changes required to improve oxygen delivery to tissue. These plastic changes are driven by shifts in gene expression patterns which may be influenced by epigenetic mechanisms. Recent studies have explored the impact of high-altitude exposure on DNA methylation in hypoxia-inducible factor (HIF) pathway genes. We expand on this work with a high-throughput investigation of methylation levels at over 850,000 CpG sites throughout the genome before and after high-altitude exposure. We hypothesized that acute high-altitude exposure would result in global hypomethylation, including reduced methylation at key HIF pathway genes including EPAS1 (HIF-2a) and EPO.DNA methylation was measured in 12 healthy participants (9 men and 3 women) between the ages of 19 and 32. DNA was isolated from whole blood collected during fasting at sea level (340m), and after 24 hours at high altitude (3800m). Illumina MethylationEPIC was used to profile methylation levels at individual CpG sites across the genome. Our preliminary analysis identified 24 differentially methylated sites (p-value threshold of 0.0001) (11 increased, 14 decreased). Of these sites, 17 were located in known gene regions. KEGG pathway analysis reveals these genes are associated with the TCA cycle (p = 0.02) and pyruvate metabolism (p = 0.03). After preprocessing, our dataset included 69 CpG sites associated with EPAS1 and 11 associated with EPO. While two EPAS1 sites show small changes in methylation status, they did not meet the significance threshold. These preliminary data suggest that DNA methylation may play a role in metabolic adaptations to oxygen limitation at high altitude.