Genome-wide DNA methylation changes after 24 hours at high altitude

High altitude presents a significant environmental stressor in the form of hypobaric hypoxia. The body responds to this condition with various acclimatization mechanisms, yet the role of epigenetic modifications, particularly DNA methylation, remains unclear. To address this gap, we investigated DNA methylation patterns in response to acute high-altitude exposure. Twelve healthy sea-level residents, aged 19-32 years, traveled to 3800 m, and DNA from peripheral blood mononuclear cells was collected both at sea level and after 24 h at high altitude. DNA methylation was assessed using the Illumina MethylationEPIC array. We identified 58,046 differentially methylated positions at high altitude compared to sea level, with a large majority of these sites showing increased methylation levels at high altitude, supporting the hypothesis that acute exposure to hypoxia may result in global hypermethylation. Notably, differentially methylated sites were located in genes enriched for pathways related to the hypoxia-inducible factor (HIF) pathway, such as "Notch signaling" and "AKT1 signaling in cancer." Moreover, several pathways associated with calcium regulation and DNA damage repair were implicated, suggesting an association between DNA methylation and calcium processes affected by hypoxia. In addition to single positions, we explored differentially methylated regions, resulting in top differentially methylated regions being associated with calcium processes, zinc finger proteins, glucose processes, and erythropoiesis. These findings provide insight into how short-term environmental hypoxia may influence the human epigenome, highlighting DNA methylation as a dynamic marker of environmental exposure.